Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23](OCC)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:20][CH2:21]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.36 (1H, br t, J=5 Hz), 8.59 (1H, d, J=1.3 Hz), 7.46 (1H, s), 7.34 (2H, m), 7.26 (1H, m), 7.20 (2H, d, J=7 Hz), 4.16 (2H, s), 4.08 (2H, d, J=7 Hz), 3.64 (2H, q, J˜5 Hz), 3.58 (2H, t, J˜5 Hz), 3.40 (3H, s), 1.00 (1H, m), 0.46 (2H, m), 0.39 (2H, m); HRMS calcd for C23H25N3O4+H+: 408.1923. Found: 408.1914.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([F:20])[C:15]([F:19])=[C:16]([F:18])[CH:17]=2)[CH3:11])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)c(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(F)cc1)c1cccc(N)c1)c1cc(F)c(F)c(F)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 3.30 g of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 3.96 g of nickel chloride hexahydrate and 1.25 g of sodium borohydride were reacted, to obtain 1.25 g of isomer A and 975 mg of isomer B of the title compound as pale yellow oils, respectively.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:31])[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])=[O:11]>O1CCCC1.C(OCC)C>[CH3:31][N:8]([CH2:9][CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])[OH:11])[CH3:7]
Reactant: CCc1noc(C)c1-c1c(C(=O)C(=O)N(C)C)c2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1noc(C)c1-c1c(C(O)CN(C)C)c2ccccc2n1C

Procedure:
A suspension of 9.24 g (0.243 mole) of lithium aluminum hydride and 500 ml tetrahydrofuran under nitrogen is heated to reflux and is treated by rapid addition with 18.47 g (0.054 mole) of N,N,1-trimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide in 350 ml of tetrahydrofuran. The resulting mixture is heated an additional 15 minutes, cooled, diluted with 350 ml of diethylether and is quenched by the dropwise addition of 60 ml of saturated magnesium sulfate solution. The mixture is then filtered through celite and the filter cake is washed with tetrahydrofuran methylene chloride and methanol. The filtrate is evaporated in vacuo and the residue chromatographed on silica gel using acetone as an eluant to give α-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1-methyl-indole-3-methanol m.p. 119° to 121° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[C:12]([CH2:14][F:15])[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][CH2:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(CF)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(CF)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of (4-fluoromethylpyrimidin-2-yl)carbamic acid tert-butyl ester (140 mg, 0.62 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour then concentrated under reduced pressure. The residue was purified by SCX-2 chromatography (washing with methanol and eluting with 2M ammonia in methanol) to afford the title compound as a yellow solid (78 mg, quant. yield). 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.1 Hz, 1H), 6.79-6.78 (m, 1H), 5.33-5.30 (m, 1H), 5.21-5.19 (m, 1H), 5.13 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:12][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[C:2]([I:1])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: NCCCCCCCCc1ccccc1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1

Procedure:
The title compound was prepared as a solid (0.718 g, 66%) from 3,5-diiodo-4-hydroxybenzoic acid using 8-phenyloctylamine and a procedure similar to step 2 of Example 93; 1H NMR (DMSO-d6) δ 1.17-1.36 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.60 (m, 2H), 3.20 (dd, J=5.9, 8.8 Hz, 2H), 7.10-7.21 (m, 3H), 7.21-7.30 (m, 2H), 8.21 (s, 2H), 8.40 (t, J=4.4 Hz, 1H), 10.06 (s, 1H); mass spectrum [(+) ESI], m/z 578 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1([CH3:11])[O:10][CH2:9]1)[C:5](=O)[CH3:6])[CH:2]=[CH2:3]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][C:8]1[O:10][CH:9]=[C:5]([CH3:6])[C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCC(C(C)=O)C1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCc1c(C)coc1C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
3-Allyl-4-methyl-4,5-epoxy-pentan-2-one (4.50 g) was added to a 1% aqueous sodium carbonate solution (150 ml), followed by stirring for 2 hours at a bath temperature of 60° to 65° C. The reaction solution was extracted three times with methylene chloride, and the methylene chloride layer was washed with an aqueous sodium chloride solution. After removing the solvent by evaporation, the residue was column chromatographed on silica gel (50 g) and developed with methylene chloride. From the first eluate (400 ml) was obtained 1.80 g of a pure objective 2,4-dimethyl-3-allylfuran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1F)[CH3:2].[CH:28]([NH2:32])([CH2:30][CH3:31])[CH3:29]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:32][CH:28]([CH2:30][CH3:31])[CH3:29])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Reactant: CCC(C)N
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC(C)CC
Yield: 167.5 %

Procedure:
4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoic acid ethyl ester (Example 2c, 1.95 g, 4.81 mmol), sec-butylamine (30 mL, 296 mmol), and dimethyl sulfoxide (20 mL) are heated in a sealed glass tube at 110° C. for 24 hours. The reaction mixture is evaporated, and purification by column chromatography (1:8, ethyl acetate/hexanes) provides the title compound as a yellow syrup (3.69 g). MS EI: m/z 458 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:21][C:19]1[O:20][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(-c2ccccc2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1oc(C)nc1-c1ccccc1)C(=O)OCC
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
60% Sodium hydride in oil (1.48 g) was added portionwise to a solution of diethyl malonate (11.7 g) in N,N-dimethylformamide (50 ml) and the mixture was stirred for 10 minutes. A solution of 5-bromomethyl-2-methyl-4-phenyloxazole (9.2 g) in N,N-dimethylformamide (20 ml) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, diluted with water, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [silica gel: 120 g; eluent: hexane-ethyl ether (3:2)] to give an oil (8.0 g) of diethyl 2-(2-methyl-4-phenyl-5-oxazolylmethyl)malonate.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[O:16]1[CH:7]2[CH2:6][C:5]3[C:10]([CH2:9][CH:8]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: C1=CCc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1ccc2c(c1)CC1OC1C2
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
To a solution of 1,4-dihydronaphthalene (8.6 g, 86% purity, 56.8 mmol) in dichloromethane (100 mL) at 0° C., m-chloroperoxybenzoic acid (17.0 g, 77% Purity, 75.8 mmol) in dichloromethane was added. After stirring for 5 h at 0° C., the solution was filtered to separate out the precipitated m-chlorobenzoic acid. The organic layer was washed with saturated Na2CO3, water, and brine (2×50 mL each). The organic layer was dried and concentrated under reduced pressure, the residue was purified by chromatography to give compound 2 (6.1 g, 73%). 1H NMR (CDCl3): δ 3.17 (d, J=17.4 Hz, 2H), 3.31 (d, J=16.8 Hz, 2H), 3.46 (s, 2H), 7.02-7.15 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(Br)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A mixture of 5-bromo-2-methylpyrimidine (119) (1.34 g, 7.75 mmol), N-bromosuccinimide (1.40 g, 7.87 mmol) and AIBN (0.13 g, 0.79 mmol) in CCl4 (15 mL) was stirred at 60° C. for 3 h. The resulting mixture was filtered, the filter cake was washed with Et2O (100 mL), and the combined filtrates were concentrated under reduced pressure. Column chromatography of the residue, eluting with 2:1 EtOAc:hexanes, gave 5-bromo-2-(bromomethyl)pyrimidine (120) (0.214 g, 11%) as a white solid: mp 55-57° C.; 1H NMR (CDCl3) δ 8.79 (s, 2H), 4.57 (s, 2H). Anal. (C5H4Br2N2) C, H, N.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].C(OC(=O)C)C.[ClH:30]>>[ClH:30].[NH:11]1[CH2:10][CH2:9][CH:8]([O:7][C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
tert-Butyl 4-(3-acetylphenoxy)piperidine-1-carboxylate (4.70 g, 14.7 mmol, Step-1) was dissolved in 4M hydrochloric acid ethyl acetate solution (30 mL). The mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was crystallized from diisopropylether to give 3.37 g (89%) of the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:22][C:15]=12
Reactant: C[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of N,N-diisopropylamine (3.6 mmol) in THF (9 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of n-BuLi (2.5M in hexanes, 3.3 mmol) was added dropwise over 3 minutes. After 30 minutes of stirring, a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.1 mmol) in THF (9 ml) was added dropwise over 9 minutes. After an additional 2 hours of stirring at −78° C., chlorotrimethylsilane (3.1 mmol) was added dropwise over 1 minute. After 1 hour of stirring at −78° C., the reaction was quenched with saturated NH4Cl(aq) (10 ml), warmed to room temperature, and partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc and the organic layers combined, washed with brine, dried (MgSO4), concentrated, and purified by silica gel chromatography (isocratic CHCl3) to give the title product as a white solid (82%). ESMS [M+H]+: 410.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>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]>[Cl:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[S:22][C:21]([C:23]4([OH:27])[CH2:26][CH2:25][CH2:24]4)=[N:20][CH:19]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Reactant: Cc1nc(Cl)ncc1Cl
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
Product: Cc1cc(Nc2ncc(Cl)c(C)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A flask was charged with a stir bar, 2,5-dichloro-4-methylpyrimidine (63 mg, 0.38 mmol), Intermediate 15 (100 mg, 0.38 mmol), Pd2(dba)3 (35 mg, 0.038 mmol), XPhos (92 mg, 0.19 mmol), and potassium carbonate (106 mg, 0.768 mmol). The vial was evacuated and backfilled with argon three times. Fully degassed tent-amyl alcohol (1.3 mL) was added to the flask, which was sealed and stirred at 90° C. overnight. The reaction was then cooled to room temperature, diluted with DCM and directly purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes) to provide 1-(5-{3-[(5-chloro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol (65 mg, 0.17 mmol, 44%) as a dark brown solid. MS ESI: [M+H]+ m/z 387.1 1H NMR (500 MHz, dmso) δ 9.81 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.51 (s, 1H), 2.58-2.50 (m, 2H), 2.45 (s, 3H), 2.37-2.27 (m, 5H), 1.93-1.82 (m, 2H). rhSYK activity=+++
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.O.[OH-].[Na+].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1Nc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 5 ml of dimethylsulfoxide, 5.35 ml of o-toluidine was added, and the mixture was heated for 24 hours at 100°-110 ° C. Water and 10%-sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. Aqueous layer was filtered and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylformamide and ethanol affording 0.19 g of the desired compound as dark yellow crystals, m.p. 277°-282° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([OH:9])=O.[Cl-].[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([NH3+:32])[CH3:31])=[CH:26][CH:25]=1)=[O:23]>>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH:32][C@H:30]([C:27]1[CH:28]=[CH:29][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][CH:26]=1)[CH3:31])=[O:9]
Reactant: O=C(O)c1c(Cl)sc(Cl)c1Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2Cc2cccc(Cl)c2)cc1

Procedure:
2,5-Dichloro-4-(3-chlorobenzyl)thiophene-3-carboxylic acid from Example 6, Step 1 (1.90 g, 5.91 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-5% EtOAc/toluene in 20 min.) to afford the desired product as a white solid. MS (−APCI): m/z 480 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Cl:14][CH2:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[Cl:13][C:3]1[C:2]([NH:1][S:16]([CH2:15][Cl:14])(=[O:18])=[O:17])=[CH:7][C:6]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([F:12])[CH:4]=1
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(=O)Nc1cc(N)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of the title compound of Step B (8.10 g, 40 mmol) in pyridine (50 mL) was added chloromethylsulfonyl chloride (3.84 mL, 40.45 mmol) over 30 minutes at 0° C. After stirring at room temperature for 14 h, chloromethylsulfonyl chloride (0.38 mL, 4.05 mmol) was added to complete the reaction. Water was added so that the product precipitated. After filtration and washing with water and petroleum ether, the title compound of Step C was isolated as a bright powder (11.17 g, 89%) melting at 208-210° C. 1H NMR (Me2SO-d6) δ 10.2-10.1 (s, 1H), 9.9 (s, 1H), 8.1 (d, 1H), 7.6-7.5 (d, 1H), 5.0-4.9 (s, 2H), 2.1 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[Br:12]Br>[OH-].[Na+]>[Br:12][C:3]1[N:4]=[CH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: BrBr
Reactant: Oc1cncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: Oc1c(Br)ncc2ccccc12
Temperature: -5 °C
Reaction time: 3 h

Procedure:
6.0 g (41 mmol) of 4-hydroxyisoquinoline are dissolved in 50 ml of 10% strength sodium hydroxide solution, giving a yellowish brown color. The reaction mixture is cooled to -5° C. using an ice/common salt mixture. A mixture comprising 6.6 g (2.1 ml, 41 mmol) of bromine dissolved in 50 ml of 10% strength sodium hydroxide solution is added dropwise to this solution over a period of 1 hour. During this period, the temperature of the reaction solution must never exceed 0° C. After this time, the coolant is removed and the reaction solution is stirred at room temperature for another 3 hours. The reaction solution is then cooled to -10° C. The reaction solution is then brought to a pH of 3 with 2N hydrochloric acid, during which the temperature of the reaction solution never exceeds -5° to 0° C. This gives the crude product as a light yellow solid. The crude product is recrystallized from 180 ml of ethyl acetate.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH:29]4[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:31]1[CH2:30][CH:29]([CH2:28][CH2:27][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][NH:10][C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:32]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCC4CNC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a pale yellow solution of tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (43 mg, 64.6 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 500 μL, 6.49 mmol00), the reaction mixture turned orange and was stirred at 25° C. for 18 h. The reaction mixture was concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid which was dissolved in dichloromethane (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane added to allow solid formation, off-white solid separated by decantation and dried under high vacuum to give 2-(1-(2-(azetidin-3-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 52.8 μmol, 81.8%). MS (M+H)+=436; 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.48 (dd, J=8.7, 5.3 Hz, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.77 (dd, J=9.8, 1.9 Hz, 1H), 7.16 (td, J=9.1, 1.9 Hz, 1H), 4.49 (t, J=6.6 Hz, 2H), 3.68-3.85 (m, 2H), 3.44-3.56 (m, 2H), 2.75 (dt, J=15.2, 7.7 Hz, 1H), 2.20 (q, J=6.7 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:5]2.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:5]2[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)C1Nc2cc(Br)ccc2-n2cccc21
Product: COc1cccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C(C)(C)C)c1

Procedure:
7-Bromo-4-tert-butyl-5-(3-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-tert-butyl-4,5-dihydropyrrolo[1,2-a]quinoxaline and m-anisoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 439/441 ([M+H]+); HRMS: calcd for C23H23BrN2O2, 438.0943; found (ESI+), 439.10084.