Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21](F)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>C1COCC1>[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of lithium diisopropylamine (49.0 mL, 2 M in THF/heptane) in THF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol) at −78° C. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2 mmol) in THF (60 mL) was added. The dry-ice bath was removed and the reaction mixture stirred for 4 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (75 mL), and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by trituration with boiling CH2Cl2 gave 7.24 g (66%) of the desired acid (3) as a yellow solid
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[C:19]12([C:26](Br)=[O:27])[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>>[C:19]12([C:26]([N:11]3[C:5]4=[N:6][C:7]5[C:2]([C:3](=[O:18])[N:4]4[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=4)=[CH:1][CH:10]=[CH:9][CH:8]=5)=[O:27])[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2
Reactant: O=C(Br)C12CCC(CC1)C2
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: O=C(n1c2ccccc2n2c(=O)c3ccccc3nc12)C12CCC(CC1)C2

Procedure:
6-(Bicyclo[2.2.1]heptanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and bicyclo[2.2.1]heptanoyl bromide.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:4].S(Cl)([Cl:17])(=O)=O>CCCCCCC>[Cl:17][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(C(=O)C(C)C)c(C)c1
Solvent: CCCCCCC
Product: Cc1ccc(C(=O)C(C)(C)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,2′,4′-Trimethylpropiophenone (30.0 g, 0.17 mole) was dissolved in heptane (10 ml), and sulfuryl chloride (35 g, 0.26 mole) was added at once. After about 5 min gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (200 ml) and was washed with 150 ml of a 2 wt % aqueous sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2,2′,4′-trimethylpropiophenone was 35.5 g or 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:60](=[N:63]O)([NH2:62])[CH3:61]>CN(C)C=O.O>[NH:62]=[C:60]([NH:63][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:7]2[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)[CH3:61]
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(OC)n2)cc1
Reactant: CC(N)=NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)NC(C)=N)c3)nc(OC)n2)cc1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid (200 mg, 0.53 mmol, Example 35(a)] in dimethylformamide (1.75 mL) is added diisopropylethylamine (0.23 mL, 1.33 mmol) followed by TBTU (205 mg, 0.64 mmol). Stirred the solution for 15 minutes before adding acetamide oxime (59 mg, 0.8 mmol). After 4 hours of stirring at ambient temperature the mixture is diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic extracts are washed three times with water (20 mL), with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide N-(1-imino-ethyl)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [60 mg, 69%, Intermediate (45)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>CN(C)C=O>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]=1[C:20]#[N:21]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(F)c2C#N)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
4-Methoxybenzyl alcohol (5.0 g) and cesium carbonate (8.3 g) were added to an N,N-dimethylformamide (0.5 L) solution of 2,6-difluorobenzonitrile (7.0 g), and stirred for 15 hours. The reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate, dried with sodium sulfate, and concentrated under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (6.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc3c(c2)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3c(c2)OCO3)sc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(α-hydroxy-3,4-(methylenedioxy)benzyl]-thieno[2,3-b]pyridine-3-sulfonamide (0.10 g, 0.18 mmoles)[see Example 4(B)] and triethylsilane (0.29 ml, 1.8 mmoles) in CH2Cl2 (2 ml) was added boron trifluoride etherate (0.10 ml, 0.81 mmoles). The orange-brown solution was stirred 2 hours at ambient temperature then diluted with EtOAc (50 ml) and washed with H2O (75 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect an orange oil. Flash chromatography (40% EtOAc/hexanes) provided 66 mg (66%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7](=[O:9])[O:8][C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CSC[C@H](O)C(=O)O
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC[C@H](OC(=O)[C@H](C)CSC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
(S)-3-(Acetylthio)-2-methylpropanoic acid (0.38 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (0.38 g, 2.35 mmol) were stirred under nitrogen, in tetrahydrofuran (10 ml). After 30 min, a solution of (R)-2-hydroxy-3-(methylthio)propanoic acid (0.32 g, 2.35 mmol), triethylamine (0.33 ml, 2.35 mmol) and tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at 25° for 18 h before evaporation of the solvent. The residue was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and the solvent evaporated. Chromatography on silica with dichloromethane/ethyl acetate as eluant gave the sub-title compound (0.1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][CH:10]=3)=[CH:3][CH:2]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=[N:30]OC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)C(C)C)C.[NH2:50][C@@H:51]([CH2:56][CH2:57][CH2:58][NH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:52](OC)=[O:53]>CN(C=O)C>[C:60]1([NH:59][CH2:58][CH2:57][CH2:56][CH:51]([NH:50][C:16]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:15]3)=[O:18])[C:52]([NH2:30])=[O:53])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COC(=O)[C@@H](N)CCCNc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(CCCNc1ccccc1)NC(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.63 g (2.64 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid, prepared as in process variant B), was suspended in 150 ml of DMF and admixed successively with 1.01 g (3.08 mmol) of TOTU and 0.63 ml (3.71 mmol) of ethyidiisopropylamine. The mixture was stirred at RT for 20 min, and 0.73 g (3.28 mmol) of methyl (S)-2-amino-3-phenylaminoethylpropionate, prepared according to a), was added to the resulting clear solution. The mixture was stirred under reduced pressure for 15 h and the methyl ester of the title compound was then isolated by flash chromatography over silica gel (DCM:MeOH=19:1). Yield: 0.44 g, empirical formula C26H26N4O3; M.W.=442.2; MS (M+H) 443.3.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])[C:18]2[N:17]=[CH:16][C:15](=[O:27])[NH:14][C:13]=2[N:12]=1.[OH2:28].[OH:29]OS([O-])=O.[K+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[N:20]=[C:19]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])[C:18]2[N:17]=[CH:16][C:15](=[O:27])[NH:14][C:13]=2[N:12]=1)(=[O:29])=[O:28]
Reactant: O=S([O-])OO
Reactant: O
Reactant: O=c1cnc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2[nH]1
Agent: [K+]
Solvent: CC#N
Product: O=c1cnc2c(NC(CO)CO)nc(S(=O)(=O)Cc3cccc(F)c3F)nc2[nH]1

Procedure:
2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[-2-hydroxy-1-hydroxymethylethyl]amino]-7(8H)-pteridinone (2.25 g) was stirred in acetonitrile (750 ml) and water (750 ml) with oxone (22.5 g) for 18 hrs. Acetonitrile was removed in vacuo to leave an aqueous suspension. The mixture was extracted into ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and the solvent removed in vacuo to afford the subtitled compound (1.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[C:8]=2[NH2:12])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([CH3:26])[CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([CH3:26])[CH2:23][C@H:22]1[C:27](=[O:28])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:13])=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: Nc1ccc2cc(Br)ccc2c1N
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
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: C[C@H]1C[C@@H](C(=O)Nc2c(N)ccc3cc(Br)ccc23)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g)
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>>[SH:24][CH2:23][CH2:22][CH2:21][S:25][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: SCCCS
Product: CC1(c2ccccc2)OC(CC(SCCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,3-propanedithiol to provide 5-[2-[(3-mercaptopropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.65 and 1.68 (singlets, 3H), 2.41 (m, 2H), 1.73-2.20 (overlapping multiplets, 3H), 2.45-2.65 (m, ˜4H) 3.08-3.27 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.27-7.45 (m, 6H); MS (HR-FAB) m/z 391.0850 (M+H calcd. for C20H23O2S3 391.0860).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.[OH-:23].[Na+:24]>O>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[OH2:23].[OH2:3].[OH2:3].[Na+:24]
Reactant: [OH-]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Agent: [Na+]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1
Temperature: 60 °C

Procedure:
0.97 g (2.9 mmols) of topiramate (Cheminor Ltd.), 10 mL distilled water, and 2.8 mL 1N NaOH (2.8 mmol) were added to a glass beaker, warmed on a hotplate to 60° C. and stirred with a TEFLON-coated stir bar on a magnetic stirplate. The solid topiramate dissolved in about 25 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[CH3:23][CH2:24][N:25](C(C)C)[CH:26](C)[CH3:27].C1C=C[C:35]2[N:40](O)N=[N:38][C:36]=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:25]1[CH2:26][CH2:27][N:40]2[CH:35]=[CH:36][N:38]=[C:23]2[CH2:24]1)=[O:12])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Yield: 64.9 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-c]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DIPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H) 3.88-4.16 (m, 5H), 4.73 (s, 1H), 4.85 (m, 1H) 5.26-5.39 (m, 1H) 6.90 (bs, 1H), 7.06 (m, 2H), 7.24 (m, 1H). ESI-MS 489 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>O>[CH3:11][N:12]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNC
Solvent: O
Product: CN(C)c1ccc(C(=O)O)cn1

Procedure:
6-Chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine 10 ml, 40% in water) were heated in a sealed pressure vessel at 130° C. for 6 h. The solvent was then removed and the residue was taken up in water and the pH was adjusted to 4-5. Extraction with dichloromethane yielded the pure intermediate depicted above (0.1 g, 20%).
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:26]2[CH:25]=[N:24][C:23]([NH:22][CH3:21])=[CH:28][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1ccc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.68 mmol) in toluene (20 mL) and EtOH (7 mL) were added N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 12 (1.44 g, 3.36 mmol in theory) and 2 N Na2CO3 aq. (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.2 g, 0.168 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-2) (0.020 g, 3.2%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 99.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (154 mg, 0.223 mmol) prepared in Example 158c, triethylsilane (0.20 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield the title compound (120 mg, 99%) as a colorless oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3B(O)O)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51](Br)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 14 h
Yield: 43 %

Procedure:
A solution of 21.7 g (50.2 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 6 in 80 mL of ethanol and 130 mL of toluene was added to a mixture of 5 g (4 mmol) of tetrakis (triphenylphosphine) Pd(0), 16.75 g (45.8 mmol) of 1,4-dibutyl-1,3-dihydro-3-[(6-bromo-3-pyridinyl)methyl]-2H-imidazol-2-one from step 5, 225 mL of toluene, 100 mL of 2M sodium carbonate, and 150 mL of ethanol. The reaction mixture was heated to reflux and vigorously stirred under nitrogen for 14 h. The pH was adjusted to 6 with acetic acid and the reaction concentrated in vacuo. The product was.purified by silica gel chromatography (Waters Prep-500A) using 2-propanol/methylene chloride (0-50%) followed by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (30-35:70-65) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, and the water extracted 4 times with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo. Recrystallization from ethyl acetate gave 8.5 g (43%) of colorless 1,4-dibutyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one as a colorless solid: mp 170°-171° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 3H), 0.96 (t, J=7 Hz, 3H), 1.28-1.54 (m, 6H), 1.61-1.72 (m, 2H), 2.28 (t, J=8 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 4.96 (s, 2H), 5.96 (s, 1H), 7.36 (d, J=9 Hz, 1H), 7.47-7.58 (m, 3H), 7.67 (dd, J=9 and 2 Hz, 1H), 8.06-8.13 (m, 1H), 8.52 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 432 (100), 404 (18), 237 (14), 209 (92), 180 (82); HRMS. Calc'd for M+H: 432.2512. Found: 432.2554. Anal. Calc'd for C24H29N7O: C, 66.80; H, 6.77; N, 22.72. Found: C, 66.59; H, 6.85; N, 22.57.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:22]([OH:25])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.[CH3:26][N:27]=[C:28]=[O:29].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([CH:22]([O:25][C:28](=[O:29])[NH:27][CH3:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:6]=2[N:7]=1
Reactant: CN=C=O
Reactant: CCC(O)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCC(OC(=O)NC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-propan-1-ol(62 mg, 0.184 mmol), methyl isocyanate (0.25 ml), dimethylaminopyridine (20 mg) in dichloromethane (2 ml) was heated at reflux for 1 hr. Additional methyl isocyanate (0.25 ml) was added and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give a yellow foam (95 mg). The foam was purified by preparative thin layer chromatography plate in 10% methanol in chloroform, then in 20% methanol in chloroform as solvent to give the title compound (29 mg) as an off-white solid.