Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:38][C@H:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=4)[CH3:37])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cn1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A suspension of 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile (Method 32, 5.75 g, 22.0 mmol), in n-BuOH (28.75 ml) was prepared at room temperature in a 48 ml sealed tube. DIEA (4.98 ml, 28.6 mmol) was then added, followed by the addition of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 4.0 g, 28.6 mmol). The tube was then sealed, and the suspension was heated to 130° C. over 45 minutes. The reaction was then allowed to stir at 130° C. for 18 hours. The reaction was then cooled to room temperature and concentrated by rotary evaporation at 60° C. to remove n-BuOH. The remaining oil was then taken up in DCM (100 ml) and washed with water (2×100 ml). The combined aqueous fractions were then extracted with DCM (100 ml), and the combined organic fractions were dried over Na2SO4, filtered and concentrated. The resulting oil was then purified by column chromatography (DCM, then DCM-MeOH=100:1) to give the title compound (5.2 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=2.5 Hz, 1H), 7.60-7.34 (m, 3H), 6.09-5.63 (m, 1H), 5.24 (q, J=7.0 Hz, 1H), 1.91 (septet, 1H), 1.58 (d, J=6.6 Hz, 3H), 1.08-0.90 (m, 2H), 0.79-0.70 (m, 2H). MS: Calcd.: 381. Found: [M+H]+ 382.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7](=[O:19])[C:6]=2[N:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:7](=[O:19])[C:6]3[N:20]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:3]=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1c2nc(Br)ccc2OCN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cc3)CO4)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (110 mg, 0.33 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (149 mg, 0.30 mmol) and K3PO4.3H2O (237 mg, 0.89 mmol) in dioxane/H2O (5 mL/0.2 mL) were added Pd2(dba)3 (13 mg, 0.02 mmol) and X-phos (14 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (DCM:MeOH=100:1) to afford the product of 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (170 mg, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 7.94˜7.97 (m, 3H), 7.75˜7.77 (m, 1H), 7.62 (s, 1H), 7.42˜7.45 (m, 1H), 7.33˜7.36 (m, 2H), 7.19 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.6 Hz, 2H), 6.05 (br s, 1H), 5.22 (s, 2H), 4.78 (s, 2H), 3.22 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.93 (s, 3H). MS (M+H)+: 633.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]O.C(O)(=O)C.[BrH:25]>C(OCC)C>[BrH:25].[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Br:25]
Reactant: Nc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
3-Amino-4-benzyl-5-sulfamylbenzyl alcohol (12.5 g; prepared as described in Example 4) is while stirring added in portions to acetic acid saturated with dry hydrogen bromide (60 ml), and the mixture is stirred for 24 hours. The resulting solution is diluted with diethyl ether (150 ml) and cooled to precipitate 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide as a hygroscopic material with a melting point of 195°-198° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(CO)(CO)C(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (10.06 g, 75 mmol) in MeOH was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether and stirred at room temperature overnight. After solvent was concentrated under reduced pressure, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate as an oil (3.79 g, 34%). 1H NMR (300 MHz, CDCl3) δ 3.81 (d, 2H), 3.67 (s, 3H), 3.60 (d, 2H), 2.89 (br, 2H), 0.96 (s, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][N:30]([S:38]([CH3:41])(=[O:40])=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][N:30]([C:31]1[CH:32]=[CH:33][C:34]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:35][CH:36]=1)[S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccc(C(F)(F)F)cc21
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc(C(F)(F)F)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH:28]([N:31](CC)C(C)C)(C)C.BrC#N.O>ClCCl>[C:28]([N:23]1[CH2:22][CH2:21][C:20]2([CH2:19][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:26]2)[CH2:25][CH2:24]1)#[N:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Agent: N#CBr
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt, 0.22 g) and N,N-diisopropyl-ethylamine (0.22 mL) in dichloromethane (20 mL) is stirred at room temperature for 5 min. Bromocyanide (60 mg) is added and the solution is stirred at room temperature for 2 h. Water is added and the mixture is extracted with dichloromethane. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:5:0→5:4:1) to give the title compound. Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:19]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([S:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=2)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Product: CC(C)(C)OC(=O)NCCOc1cccc(NS(=O)(=O)C2CCCCC2)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using cyclohexanesulfonyl chloride (8) following the method described in Example 1 gave tert-butyl 2-(3-(cyclohexanesulfonamido)phenoxy)ethylcarbamate (9) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.75-6.78 (m, 2H), 6.59-6.62 (m, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.24 (q, J=6.0 Hz, 2H), 2.89-2.98 (m, 1H), 1.92-2.01 (m, 2H), 1.68-1.76 (m, 2H), 1.52-1.57 (m, 1H), 1.31-42 (m, 11H), 1.05-1.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[Cl:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[C:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 29.1 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (1 g, 3.4 mmol), p-fluorophenylsulfonyl chloride (1.33 g, 6.8 mmol) and Eaton's reagent (20 mL) was stirred at 110° C. for 4.5 h and the solution turned brown. The brown solution was poured into ice water and extracted with EtOAc (3×30 mL). The combined extracts were washed with sat'd sodium bicarbonate (3×50 mL), brine (50 mL), dried and concentrated. The residue was purified by chromatography (20% EtOAc in Hexanes) to give the title compound of Step A (468 mg). MS (APCI−) Calc.: 471.0, Found: 470.0 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6][NH2:7])=[C:4]([CH3:11])[CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH2:6][N:7]=[C:13]=[O:15])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Br)cc(C)c1CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc(Br)cc(C)c1CN=C=O

Procedure:
The title compound was prepared from 4-bromo-2,6-dimethyl-benzylamine and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 1. Mass spectrum (EI): m/z=239/241 (Br) [M]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[NH:8][NH2:9])#[N:2].Cl>CO.C(OCC)(=O)C>[NH2:2][C:1]1[C:3]2[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=2[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)c1cc(C#N)c(NN)s1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A mixture of tert-butyl 4-cyano-5-hydrazinothiophene-2-carboxylate (1.0 g, 4.2 mmol) and hydrochloric acid (0.7 mL of 37% solution) in methyl alcohol (15 mL) was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with an aqueous solution of sodium bicarbonate. Organic layer was separated, dried over anhydrous sodium sulfate, and evaporated to give 0.9 g of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:9](=[O:11])[C@@H:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:28][CH2:29]2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (0.556 g, 2.62 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.378 g, 1.31 mmol) in dry DMF (7 mL) was treated with Triton® B (2.40 mL, 5.28 mmol, 40 weight percent solution in methanol), a clear solution was obtained. The resulting reaction solution was cooled to 0° C. in an ice-water bath. To this solution was added solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.993 g, 2.62 mmol). After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution. White solid which forms was removed by filtration. The two layers of the filtrate were separated; the organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (30% EtOAc in hexanes) affording 0.48 g (76%) of the pure titled compound as a white foam: mp 45-54° C. APCI-MS m/z 484.4 (MH+).
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(NCCOC)=NC=1.[CH:40]1([CH2:43][NH2:44])[CH2:42][CH2:41]1.[Br:45][C:46]1[C:47]([C@@H:56]([NH:66][C:67](=[O:85])[CH2:68][N:69]2[C:77]3[C:76]([F:79])([F:78])[CH2:75][CH2:74][C:73]([F:81])([F:80])[C:72]=3[C:71]([CH:82]([F:84])[F:83])=[N:70]2)[CH2:57][C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[C:60]([F:65])[CH:59]=2)=[N:48][C:49](S(C)(=O)=O)=[N:50][CH:51]=1>>[Br:45][C:46]1[C:47]([C@@H:56]([NH:66][C:67](=[O:85])[CH2:68][N:69]2[C:77]3[C:76]([F:78])([F:79])[CH2:75][CH2:74][C:73]([F:80])([F:81])[C:72]=3[C:71]([CH:82]([F:84])[F:83])=[N:70]2)[CH2:57][C:58]2[CH:59]=[C:60]([F:65])[CH:61]=[C:62]([F:64])[CH:63]=2)=[N:48][C:49]([NH:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)=[N:50][CH:51]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: NCC1CC1
Agent: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCC2CC2)ncc1Br

Procedure:
The title compound (13A) was prepared according to the method presented for the synthesis of compound 11I of Example 11 utilizing cyclopropylmethanamine and 12C. MS (m/z) 668.95 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[C:10]=1[F:19])C1C=CC=CC=1.[CH3:20]OC(OC)N(C)C>[Pd]>[F:19][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]2[C:11]=1[CH:18]=[CH:20][NH:15]2
Reactant: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Reactant: COC(OC)N(C)C
Agent: [Pd]
Product: Oc1ccc2[nH]ccc2c1F
Temperature: 180 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene (5 g, 19 mmol) is dissolved N,N-dimethylformamide dimethyl acetal (15 mL) and heated in a microwave reactor at 180° C. in a sealed vial for 1 hour. The solution is then concentrated under reduced pressure. The resulting residue is dissolved in THF and Pd/C (1.0 g, 10%, 0.95 mmol) is added. The mixture is stirred under a hydrogen atmosphere at room temperature for 16 h before being filtered through a pad of Celite® and concentrated. The residue is separated by FCC (EtOAc/heptane from 0 to 40%) to give 4-fluoro-1H-indol-5-ol (1.5 g, 52% yield). MS (ESI) m/z 152.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s., 1H), 8.79 (s, 1H), 7.26 (t, J=2.78 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 6.75 (t, J=8.46 Hz, 1H), 6.34 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:2][C:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[O:16][CH2:15][CH2:14][O:3]1
Reactant: CCOC(=O)c1cc(C(C)=O)on1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2(C)OCCO2)on1
Yield: 100.1 %

Procedure:
A reaction mixture consisting of ethyl 5-acetylisoxazole-3-carboxylate (2.53 g, 13.8 mmol), ethylene glycol (1.29 g, 20.7 mmol) and p-TsOH (0.13 g, 0.69 mmol) in benzene (50 mL) was refluxed with the Dean-Stark adapter for 24 hours (scheme 59). Most of the solvent was removed under reduced pressure and the residue was partitioned between saturated NaHCO3 and EtOAc. Organic layer was collected, washed with brine, water, and dried over MgSO4. Evaporation of the dried extract under reduced pressure afforded the title compound as an oil (3.14 g, 100% yield), which was used for next step without further purification. 1H NMR (DMSO-d6) δ (ppm): 6.89 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.07-4.01 (m, 2H), 4.01-3.94 (m, 2H), 1.70 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS (m/z): 227.21 (calc) 228.1 (MH+) (found).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]([C:50]1[S:51][C:52]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54][C:53]=2[N:59]=1)([CH3:49])[CH3:48]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:56]3[CH2:57][CH2:58][C:52]4[S:51][C:50]([CH:47]([CH3:49])[CH3:48])=[N:59][C:53]=4[CH2:54][CH2:55]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(C)c1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 0.25 mmol 6-chloro-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.30 mmol HATU, 1.27 mmol DIPEA and 0.51 mmol 2-isopropyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in 1 mL DMF. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 24 mg (25% of theory). ESI-MS: m/z=376 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([O:40]CC2C=CC=CC=2)=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CCC(=O)O)c1
Yield: 87.2 %

Procedure:
Next, 0.68 g (1.03 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(2-benzyloxycarbonylethyl)phenyl](methyl)phosphono}butanoate was dissolved in 50 mL of a solvent mixture of methanol and water at 4:1 and mixed with 240 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(2-carboxyethyl)phenyl](methyl)phosphono}butanoic acid (0.31 g, yield 86%) as a colorless solid.
Reaction SMILES: [CH3:1][N+]1([O-])CCOCC1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]=[O:24])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[Mg]Cl>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]([OH:24])[CH3:1])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=CC[C@H]1CN(Cc2ccccc2)CCN1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[Mg]Cl
Product: CC(O)C[C@H]1CN(Cc2ccccc2)CCN1

Procedure:
Briefly (and essentially as described in PCT International Publication Numbers WO 98/20001 and WO 99/65922), (Nα-(t-butyloxycarbonyl)-β-(benzyl ester)-L-aspartic acid) is reacted with N-benzylglycine in the presence of DCC and HOBt to produce the corresponding N-benzylglycine amide, which is further reacted with TFA to remove the BOC protecting group, yielding ((S)-4-benzyl-3,6-dioxo-piperazin-2-yl)-acetic acid ethyl ester. This is reduced to 2-((S)-4-benzyl-piperazin-2-yl)-ethanol by reaction with LiAlH4 in THF. Essentially as described in PCT International Publication Number WO 02/094799, the free amine is reacted with (BOC)2O to produce the corresponding carbamate, and the primary alcohol is oxidized with catalytic TPAP in the presence of NMO to the corresponding aldehyde, ((S)-4-benzyl-piperazin-2-yl)-acetaldehyde. This is reacted with MeMgCl under Grignard reaction conditions to produce the secondary alcohol, 1-((S)-4-benzyl-piperazin-2-yl)-propan-2-ol, as a mixture of diastereoisomers, which is oxidized to the corresponding methylketone, 1-((S)-4-benzyl-piperazin-2-yl)-propan-2-one, by reaction with catalytic TPAP and NMO. The methylketone undergoes a tandem aldol condensation/Michael conjugated addition by reaction with 1-(4-methoxy-2,3-dimethylphenyl)-ethanone in the presence of LiCl and DBU as a base in THF as the solvent, yielding bicyclic (6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethyl-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one. This is deoxygenated to (6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine by conversion to the corresponding tosylhydrazone and subsequent reduction with NaBH3CN in the presence of zinc triflate. The benzyl group is removed by catalytic transfer hydrogenation reaction promoted by Pd(OH)2 in the presence of excess ammonium formate in MeOH. Finally, (6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine is converted to the desired heteroaroyl analog by reaction with the corresponding acid chloride under Schotten-Bauman reaction conditions.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH:7]([CH2:18][O:19][CH3:20])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9]>C(#N)C>[C:1]([O:4][CH:7]([CH2:18][O:19][CH3:20])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COCC(Br)C(=O)Nc1ccc(C)cn1
Agent: [K+]
Solvent: CC#N
Product: COCC(OC(C)=O)C(=O)Nc1ccc(C)cn1
Yield: 88.9 %

Procedure:
Potassium acetate (2.01 g, 20.50 mmol) was added to a stirred solution of 2-bromo-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (Step 1) (1.40 g, 5.13 mmol) in ACN (20 mL). The reaction mixture was refluxed for 5 hrs. The reaction mixture was filtered and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (1.15 g), 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.11 (m, 2H), 7.52 (dd, 1H), 5.44 (dd, 1H), 3.89 (dd, 1H), 3.78 (dd, 1H), 3.39 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H).