Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Br>C(O)C>[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[N:4]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Nc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)nc(SCc2c(F)cccc2F)n1
Temperature: 22 °C

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimdine monohydrate (1.61 g, 10.0 mmol) is suspended in 50% ethanol (10 ml), then treated with solid sodium hydroxide (440 mg, 11.0 mmol) and stirred until the solid dissolved. 2,6-Difluoro-benzyl bromide (2.17 g, 10.5 mmol) is added and the reaction heated to reflux for 1.5 hrs. After cooling to 22° C., the solid is collected, washed with water, then air dried. The title compound is recrystallized from ethanol, mp 245-246° C.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH:7]([CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)[CH:14]=[N:13]1)[C:8]([OH:10])=[O:9].[CH3:35]O>O>[OH:6][C@H:7]([CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)[CH:14]=[N:13]1)[C:8]([O:10][CH3:35])=[O:9]
Reactant: CO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(O)C(=O)O)c2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (0.10 ml, 1.83 mmol) was added to an oven-dried vial containing 2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid (1.78 g, 1.83 mmol) in MeOH (12.2 ml) and the solution was warmed to 70° C. and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford racemic methyl (2R)-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate. The racemic sample was purified by super critical fluid chiral chromatography (AD-H 2.1×25 cm, 5 μm, 45%/55% 2-propanol/CO2, 70 mL/min, 12 min. run time, 220 nM) to afford (R or S) 2-methyl-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (early eluting enantiomer). MS ESI calcd. for C19H19F3N5O3 [M+H]+ 422. found 422.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]1([CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:24][C:23]1[C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:20]([CH3:21])[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)C(C(C)=O)c1ccccc1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-phenylpentane-2,4-dione: MS (ESI) m/z 293 [M+H]+, 1H-NMR (CDCl3) δ 7.45-7.27 (9H, m), 3.79 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.26 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:26]1[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]1)[CH2:6][CH2:5]2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Reactant: Clc1ccc2c(c1)CCN2
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5cc(Cl)ccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 5-chloroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:13][N:14]([CH3:19])[C:15](=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[CH:16][C:15]([N:14]([CH3:19])[CH3:13])=[O:18])=[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(C)c1cc(N)ncc1Br
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C=Cc1cnc(N)cc1C(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
De-gas a mixture of 5-bromo-4-tert-butyl-pyridin-2-ylamine (330 mg, 1.4 mol), N,N-dimethylacrylamide (0.22 mL, 2.1 mmol), triethylamine (0.4 mL, 2.1 mmol) in toluene (4 mL) while purging with nitrogen for 3 minutes. Add palladium(II)acetate (60 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (690 mg, 0.6 mmol) under nitrogen. Heat the reaction overnight in sealed vessel at 120° C. Cool the mixture to room temperature, filter through Celite® and concentrate. Purification by silica gel column chromatography (100% DCM to 3% MeOH in DCM) to yield the title compound (81% yield). LCMS (ES), m/z 248 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 88.1 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([Cl:2])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: CSc1ccc(NNC(=O)c2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(NN=C(Cl)c2ccccc2)cc1

Procedure:
A mixture consisting of 7.9 g. (0.038 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 9.05 g. (0.035 mole) benzoic acid 2-[p-(methylthio)phenyl]hydrazide (prepared in Part A above) was heated at the reflux temperature until evolution of gas ceased. The reaction mixture was chilled in ice, and a suspension of 11.3 g. (0.12 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation under reduced pressure, the resulting triphenylphosphate solution of the desired product was poured through a column of silica gel. The column was eluted with a mixture of 1 part benzene and 1 part Skellysolve B. After removing the solvents from the eluate by evaporation under reduced pressure, the residue was recrystallized two times from cyclohexane to give benzoyl chloride [p-(methylthio)phenyl]hydrazone having a melting point at 94° to 95°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[N:10]=2)[CH:7]=1
Reactant: OCc1cn2cc(Br)ccc2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To solution of (6-bromoimidazo[1,2-a]pyridin-2-yl)methanol (3.21 g, 14.13 mmol) in DCM (50 mL) was added imidazole (1.30 g, 19.09 mmol) followed by TBSCl (2.60 g, 17.25 mmol). Reaction mixture was stirred at room temperature for 30 min then was diluted with DCM (50 mL) and washed with H2O (50 mL). Organic phase was washed with NaCl (aqueous saturated, 50 mL) and dried over Na2SO4. Solvent was concentrated and residue purified by column chromatography using EtOAc/hexanes (gradient 0-50%) to afford 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridine (3.32 g) in 69% yield as pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:31]=[C:30]([NH2:32])[N:29]([CH3:33])[N:28]=2)[CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[C:31]([C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)=[C:30]([NH2:32])[N:29]([CH3:33])[N:28]=2)[CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(CN(Cc2cccc(-c3cc(N)n(C)n3)c2)C(=O)OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(CN(Cc2cccc(-c3nn(C)c(N)c3C3=CCCCC3)c2)C(=O)OCc2ccccc2)cc1
Yield: 70.8 %

Procedure:
A solution of EXAMPLE 56D (4.5 g, 10 mmol) in acetic acid (100 mL) was treated with cyclohexanone (2 mL, 20 mmol) at ambient temperature for 4 days. The mixture was concentrated and the residue partitioned between dilute sodium hydroxide and ethyl acetate. The organic layer was washed with water and concentrated and the residue purified by flash chromatography on silica gel using ethyl acetate to give 3.8 g (71%) of the title compound. MS (DCI): m/z 537 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][NH2:21])=[O:19]>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N:21][NH:20][C:18](=[O:19])[C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([O:14][C:13]([F:12])([F:26])[F:25])[CH:16]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: NNC(=O)c1cccc(OC(F)(F)F)c1
Solvent: CCO
Product: O=C(NN=Cc1cc(Cl)cc(Cl)c1O)c1cccc(OC(F)(F)F)c1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A suspension of 3,5-dichloro-2-hydroxy-benzaldehyde (0.200, 1.05 mmol) and 3-trifluoromethoxy-benzoic acid hydrazide (0.243 g, 1.05 mmol) in ethanol (3.3 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide as an off-white solid (0.412 g, 99%): mp 180-182° C.; 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4][CH:3]2[CH2:6][NH:7][CH2:8][CH:2]12.Cl[C:27]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[C:29]([Cl:37])[N:28]=1>O1CCOCC1>[Cl:37][C:29]1[N:28]=[C:27]([N:7]2[CH2:6][CH:3]3[CH:2]([N:1]([C:9]([O:11][CH2:12][CH:13]4[C:25]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CNCC21
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CN(c3nc(Cl)cc4nccnc34)CC21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The mixture of (9H-fluoren-9-yl)methyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (100 mg, 0.5 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (600 mg, 1.8 mmol) in dioxane was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 498 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([OH:12])=O.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][O:7][CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:15]=[C:2]([F:1])[CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cc(-c2cc(F)cc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCCC1)OC
Product: COC(CN(C(=O)CCOCCc1cc(F)cc(-c2cnn(C)c2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (3.3 g) was prepared from 3-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 17, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.81 and 7.80 (2×s, 1H), 7.19 (m, 1H), 7.09 (dt, J=10.0, 1.9 Hz, 1H), 6.80 (m, 1H), 4.52 and 4.36 (2×t, J=5.0 Hz, 1H), 4.00 and 3.64 (2×tt, J=3.6 and 11.7 Hz, 1H), 3.902 and 3.898 (2×s, 3H), 3.76-3.64 (m, 4H), 3.34 (s, 3H), 3.33 and 3.25 (2×d, J=5.1 Hz, 2H), 3.32 (s, 3H), 2.85 and 2.84 (2×t, J=6.2 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.69 (m, 2H), 1.68-1.49 (m, 3H), 1.49-1.19 (m, 4H), 1.16-1.01 (m, 1H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:20](N)=[NH:21]>CCOC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][N:21]=[C:4]2[OH:5]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Reactant: N=CN
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(O)c2cc1OCCCCl
Yield: 76 %

Procedure:
In the manner described in Example 16A Step 4, methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 21.9 mmol) in EtOAc from the previous step was reacted with formamidine hydrochloride as in Example 16A Step 4 to give 6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (4.48 g, 16.7 mmol, 76%). 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7.15 (s, 1H), 4.19 (t, 2H), 3.97 (s, 3H), 3.81 (t, 2H), 2.27-2.19 (m, 2H); LC-MS (ESI) m/z 269 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[O:17])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[O:17][CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(F)cc1)c1ccccc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethylsulphoxide (DMSO; 30 ml). A solution of o-chlorophenyl p-fluorophenyl ketone (0.025 mol) in DMSO (10 ml) was added dropwise at room temperature. The solution was then heated at 50° for 11/2 hours, cooled to room temperature and poured into water. The solution was extracted with diethyl ether (100 ml), washed with water (3×100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-o-chlorophenyl-1-p-fluorophenyl ethylene oxide (90%) as a colourless liquid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:18][N:17]3[C:19]3[CH:23]4OC(C)(C)OC4C(=O)C=3)=[CH:15][C:10]=2OC1>O1CCOCC1>[CH:16]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:15]=2[CH:23]=[CH:19][NH:17][CH:18]=1
Reactant: CC1(C)OC2C(=O)C=C(N3CC3c3ccc4c(c3)OCO4)C2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C1=Cc2ccccc2C=CN1
Temperature: 100 °C
Yield: 171.7 %

Procedure:
Cesium carbonate (3.2 g, 9.8 mmol, 4.0 equiv) was added to a stirred solution of aziridine 54 (770 mg, 2.4 mmol, 1.0 equiv) in 1,4-dioxane (350 mL) at 25° C. The reaction vessel was sealed under argon and heated to 100° C. via oil bath for 18 h. The reaction mixture was gravity filtered and concentrated by rotary evaporation. The residue was purified by passage through a plug of silica gel (ethyl acetate) to afford 55 (590 mg, 76% yield) as a tan foam. Rf=0.27 (50% ethyl acetate in benzene); 1H NMR (500 MHz, CDCl3) δ 7.82 (br s, 1H, ArH), 6.54 (s, 1H, ArH), 5.93 (d, 1H, J=1.5 Hz, OCH2O), 5.91 (d, 1H, J=1.5 Hz, OCH2O), 5.77 (br s, 1H, NH), 4.97 (d, 1H, J=6 Hz, CH(OR)), 4.65 (d, 1H, J=6 Hz, CH(OR)), 3.80-3.85 (m, 1H, ArCH2CH2N), 3.60-3.65 (m, 1H, ArCH2CH2N), 2.95 (br t, 2H, J=4 Hz, ArCH2CH2N), 1.44 (s, 3H, CH3), 1.43 (s, 3H, CH3); 13C NMR (125 MHz, C6D6) δ 195.02, 165.26, 146.76, 146.28, 133.02, 126.24, 113.71, 109.55, 109.10, 109.00, 100.84, 78.98, 76.30, 47.65, 36.87, 27.89, 26.87; IR (neat film) 3266 (w), 2924 (s), 2855 (m), 1705 (w), 1585 (s) cm−1; HRMS (ESI) m/z: Calcd for C17H18NO5 (MH+) 316.1185, observed 316.1189.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.CCOCC>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3C(F)(F)F)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
tert-Butyl ((1R,3S)-3-isopropyl-3-{[4-[2-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)carbamate (0.17 g, 0.00035 mol) was dissolved in a 2.0 M solution of HCl in ether (2.2 mL). After being stirred for 2 h at room temperature, the solution was concentrated to give 144 mg of desired product as a clear oil. MS calculated for C21H27F3N2O: (M+H) 381; found 381.1.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=[CH:13]2.[CH2:25]([N:32]1[CH2:37][CH:36]2[C:38](=O)[CH:33]1[CH2:34][CH2:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:25]([N:32]1[CH2:37][CH:36]2[CH:38]([NH:9][C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[N:14]=[CH:13]4)[CH:33]1[CH2:34][CH2:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C2CCC1N(Cc1ccccc1)C2
Reactant: CC(C)(C)C(=O)n1ncc2cc(N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3N(Cc3ccccc3)C4)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
To a solution of 1-(5-amino-1H-indazol-1-yl)-2,2-dimethylpropan-1-one maleate salt (580 mg, 1.7 mmol, prepared as described in U.S. Ser. No. 08/021,4614) and 2-benzyl-2-azabicyclo[2.2.1]heptan-7-one (250 mg, 1.7 mmol) (J. R. Malpass, S. Handa, and R. White, Org. Lett., 2005, 7, 2759-2762) in THF (9 mL) was added sodium triacetoxyborohydride (740 mg, 3.5 mmol), and the mixture was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by normal phase chromatography followed by reversed phase HPLC to afford 175 mg (25%) of 1-(5-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-ylamino)-1H-indazol-1-yl)-2,2-dimethylpropan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[CH:23](Br)([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(OC(C)C)cc12
Temperature: 60 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (26 g, 0.051 mol) in NMP (160 mL) was added isopropyl bromide (15 mL), then cesium carbonate (33 g, 0.101 mol) was added. The reaction mixture was stirred in a 60° C. oil bath for 20 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate (15 g, 82%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[CH3:20][NH:21][CH3:22].C(OCC)(=O)C>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: CNC
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (1.31 mmole, 0.350 g) was dissolved in 2 ml THF and cooled to 0° C. Dimethylamine (1 ml) was added. The solution was stirred at room temperature for 20 minutes. Ethyl acetate was added. The organic phase was washed with water, dried over sodium sulfate, and concentrated to yield 270 mg of 5-(2-cyanophenyl)-2-dimethylaminomethyl-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:26]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=2)=[O:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1cc(F)cc(F)c1
Reactant: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1
Product: CCN(Cc1cccc(OC)c1-c1cccc(CC(=O)OC)c1)C(=O)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 3,5-difluorobenzyl chloroformate.