Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:27])[C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:16]1[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: Cc1ccc2c(N3CCNCC3)c(F)ccc2n1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)c(F)ccc2n1
Temperature: 100 °C
Yield: 42 %

Procedure:
N,N-Diisopropylethylamine (0.15 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-6-fluoro quinoline (0.075 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.08; 1.1 eq) in dimethylformamide (3.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 42% yield (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A mixture of 3.2 g (12 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid, 1.4 ml (10 mmol) of triethylamine, 1.5 g (10 mmol) of 5-amino-1,3-dihydro-indol-2-one [Tetrahedron, 24, 1376. (1957)] 3.8 g (10 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] and 100 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 150 ml of 8% sodium hydrogencarbonate solution and 150 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 25 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and chloroform:methanol=19:1 as eluent to yield 2.67 g (68%) of the title compound. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([OH:24])[OH:25])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(O)O)P(=O)(O)O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)([O-])[O-])P(=O)(O)O)c1
Reaction time: 1 h
Yield: 38 %

Procedure:
[2-[3-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.103 g, 0.223 mmol) prepared according to Example 2 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0.177M, 2.58 ml, 0.457 mmol) was added. After one hour, the solvent was removed under reduced pressure leaving a brownish yellow solid. This solid was powdered and washed successively with anhydrous ether, tetrahydrofuran, acetonitrile, and ethanol leaving a white solid, 43.3 mg, 0.089 mmol, 38% yield; 1H NMR (D2O, relative to HOD peak at 4.64) ∂0.76 (t, J=6.9 Hz, 3H), 1.05 to 1.58 (several m, 18H), 2.35 (t, J=7.0 Hz, 2H), 7.30 (m, 2H), 7.55 (dd, J=43.8, 27.0 Hz, 1H), 7.69 (m, 2H); FAB mass spectrum m/z 443 (M-2Na+3H)+, 465 (M-Na+2H)+, 487 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12].CN(C)C=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][C:26]=1[C:35]([F:38])([F:37])[F:36].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]3=[O:12])=[O:33])=[CH:27][C:26]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CS(=O)(=O)CCn1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(2-(methylsulfonyl)ethyl)isoquinolin-1(2H)-one (30 mg, 0.0001 mol) in N,N-dimethylformamide (700 μL, 0.009 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (51 mg, 0.00021 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.000268 mol) and N,N-diisopropylethylamine (93 μL, 0.00054 mol). The reaction mixture was stirred for 16 hours at 50° C. LC-MS analysis showed the formation of the desired product. The mixture was taken up in saturated NaHCO3 solution and washed twice with ethyl acetate. The organic layer was dried with sodium sulfate, reduced in vacuo and purified via HPLC to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccccc3)c12
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (85 mg, 0.25 mmol) was mixed with K2CO3 (68 mg, 0.5 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd(Ph3)4 (14 mg, 0.01 mmol), 1 mL of 1,2-dimethoxyethane and 2 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 2 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Filtration followed by removal of the solvent in vacuo gave the crude product (71 mg), which was purified by column chromatography to give 53 mg (77% yield) of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[N:20]=1)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.C(O)(C)(C)C>[CH2:1]([O:8][C:9]([N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[N:20]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Ethyl N-[(benzyloxy)carbonyl]-N-[(6-bromopyridin-2-yl)methyl]glycinate (0.21 g, 0.52 mmol) was dissolved in methanol (5.1 mL) and tert-butanol (5.1 mL). Potassium hydroxide (2.6 mL, 2.60 mmol) was added and the reaction was heated at 60° C. for two hours. The reaction was made acidic with 1M hydrochloric acid and the product extracted with ethyl acetate. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The product was used without further purification to yield the title compound.
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:19]([N:2]1[CH2:3][CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]1=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1NCC2CCCCC12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 3 (835 mg, 6 mmol) in suspension in tetrahydrofuran (7 mL) was successively added, under an argon atmosphere, 4-dimethylaminopyridine (18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC2O (2.62 g; 12 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under vacuum. The residue was diluted with diethyl ether (20 mL) and washed with water (2×10 mL). The phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude oil was purified over silica gel chromatography (ether/heptane 1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12]1)=[O:4]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 88.9 %

Procedure:
Chloroacetyl chloride (114 mg, 1 mmol) was added to a stirred solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and triethylamine (302 mg, 3 mmol) in dichloromethane (10 ml) at ambient temperature. After 10 minutes the reaction was purified by direct chromatography on a 10 g silica Mega Bond Elut® column, eluting with dichloromethane. Relevant fractions were combined and evaporated to give the desired product (390 mg). MS (ESP): 439 (MH+) for C19H20ClFN4O5;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C1CCCN1CCO
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: O=C1CCCN1CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIb was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 1-(2-hydroxyethyl)pyrrolidin-2-one following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:14][CH3:15].B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O>>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[C:3]([CH2:14][CH3:15])[CH:4]=2)[N:12]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCc1cc(-c2noc(C)n2)ccc1Br
Product: CCc1cc(-c2noc(C)n2)ccc1-c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared as in Description 15 from 3-(4-bromo-3-ethylphenyl)-5-methyl-1,2,4-oxadiazole (D81, 0.8 g) and 4-boronobenzoic acid (0.49 g) as a cream solid (0.66 g, 71%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:27][CH2:28][CH3:29])=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C)C=O>[CH2:28]([NH:27][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH3:29]
Reactant: CCNc1cc2ncnc(NCCCCCCl)c2cc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Product: CCNc1cc2ncnc(NCCCCCN3CCSCC3)c2cc1[N+](=O)[O-]
Yield: 98.4 %

Procedure:
Thiomorpholine (6 ml, 59.7 mmol) was added to a dimethylformamide solution (30 ml) of 4-(5-chloropentylamino)-7-ethylamino-6-nitroquinazoline (2.50 g, 7.41 mmol) obtained in Reference Example 66 and the mixture was heated under reflux for 3 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (2.95 g, 98.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Solvent: CO
Product: Nc1ccc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol (142 mg, 0.73 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N2 (g). 10% Pd—C (10 mg) was added and the reaction was stirred under H2 (1 atm) at room temperature overnight. The reaction was filtered and the filtrate concentrated to yield 7-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (H-1) (113 mg, 95%). HPLC ret. time 0.58 min, 10-99% CH3CN, 5 min run; ESI-MS 164.5 m/z (MH+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
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: CC(=O)N(C)C
Product: C[C@@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g, 1.10 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g, 1 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.156 g, 1.00 mmol) and DIPEA (0.524 mL, 3.00 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude material was treated with a 10% solution of TFA in DCM (5 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.211 g, 52.9%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: Cn1ccnn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Analogous to the general method described in J. Org. Chem. 2004, 69, 8115, and Chem. Pharm. Bull, 1997, 1145. To a 2-necked flask containing 1-methyl-1H-1,2,3-triazole (1.00 g, 12.0 mmol, Intermediate 42, step a) was added THF (75 mL) and the solution was cooled between −40 to −20° C. To this colorless homogeneous solution was added n-BuLi (2.5 M in hexanes, 5.0 mL, 11.4 mmol) dropwise which afforded a dark brown viscous mixture. After stirring at 0° C. for 1 hours, a THF (10 mL) solution of 4-chlorobenzaldehyde (1.60 g, 11.4 mmol) was introduced and the reaction mixture began to be stirred freely and remained brownish. After 3 hours the reaction mixture was quenched by pouring into a saturated solution of NH4Cl and the aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil which solidified upon standing. The crude material was triturated with Et2O to provide the title compound as a brown solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:14]Cl)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>O1CCCC1>[Cl:1][CH2:2][C:3]([N:5]([CH2:14][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: c1nc[nH]n1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N(Cn1cncn1)C(=O)CCl

Procedure:
16.5 parts by weight of 2-chloro-2',6'-dimethyl-N-chloromethyl acetanilide and 9.3 parts by weight of 1,2,4-triazole are refluxed for 8 hours in 60 parts by volume of anhydrous tetrahydrofuran. After the mixture has been cooled, it is filtered, the filtrate is concentrated in vacuo, and the residue is dissolved in 60 parts by volume of chloroform, washed 3 times with water, each time with 40 parts by volume, and dried over sodium sulfate. After evaporation of the solvent in vacuo, there is isolated 21.0 parts by weight of 2-chloro-2',6'-dimethyl-N-(1,2,4-triazol-1-yl-methyl)-acetanilide, m.p.: 115°-118° C.; after recrystallization from ethanol, it melts at 120° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH:19]([OH:22])[C:18](=[O:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2.[Li].N>>[CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[C@@H:18]([OH:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C(O)[C@]3(C)[C@H]1[C@@H]2C
Agent: N
Agent: [Li]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,25R)spirostan-3,12-diol-11-one was converted into the title compound via reduction with lithium and ammonia according to the procedure described in J. Am. Chem. Soc., 1953, 75, 1282.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([CH:11]=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:25])[O:4][N:3]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[Br:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:25])[C:15]2[O:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:13]3[C:14]=2[C:10]=1[CH:11]=[N:12]3
Reactant: Cc1noc(C)c1-c1ccc2cnn3c2c1OCC3c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(C)c1-c1cc(Br)c2cnn3c2c1OCC3c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole (0.011 g, 0.033 mmol) in acetonitrile (0.4 mL) at 0° C. was treated with N-bromosuccinimide (8.3 mg, 0.047 mmol) and stirred at 0° C. for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (20 mL), dried over sodium sulfate, filtered, and concentrated to a colorless residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave desired product (9 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (s, 1H), 7.16-7.05 (m, 2H), 5.99-5.89 (m, 1H), 4.81 (dd, J=11.7, 3.4 Hz, 1H), 4.71 (dd, J=11.6, 4.8 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H); LCMS calculated for C20H17BrN3O2 (M+H)+: m/z=410.0, 412.0. found: 410.0, 412.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(N[C@H]2CCN(Cc3ccccc3)C2)c(F)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)C(=O)N(c1ccc(F)cc1F)[C@H]1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a solution of (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine (150 mg, 0.52 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (7 mL) was added isobutyryl chloride (0.16 mL, 1.5 mmol) at 0° C. After being stirred at 60° C. for 18 h, the reaction mixture was quenched with an aqueous NaH(CO)3 solution and extracted with EtOAc. The extracts were concentrated in vacuo, the reside was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (160 mg, 86.0%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.43 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.062 g, 8%). MS (ISN) 518.3 [(M−H)−]; mp 281° C.