Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[C:10](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][C:18]\2=[O:19])[CH:9]=[N:8]1)=[O:5])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[C:10](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:16][CH2:17][CH:18]\2[OH:19])[CH:9]=[N:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (6.08 g) in ethanol (100 ml) was added sodium borohydride (230 mg). The resulting mixture was stirred at room temperature for 30 minutes, and the reaction was stopped by addition of a saturated aqueous ammonium chloride solution. The products were extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford the title compound as a yellow amorphous solid (6.2 g, yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([O:23]CC)=[O:22])=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([OH:23])=[O:22])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cccn2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of ethyl 2-chloro-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxylate (275 mg, 0.761 mmol) in THF (4 mL), aq. 1N LiOH (1.25 mL, 1.25 mmol) was added. The mixture was stirred at room temperature overnight. Upon acidification of the mixture with 1N HCl, white solids precipitated out, which were collected, and dried on vacuum to give 2-chloro-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxylic acid (230 mg). MS 334.3 and 336.3 (M+H, Cl pattern)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1>C(#N)C.C(N(CC)CC)C>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 99 %

Procedure:
2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (0.20 g) obtained in Example 73c) was dissolved in acetonitrile (10 ml). HOBt (0.19 g), WSC (0.24 g), triethylamine (0.16 ml) and 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.24 g) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.36 g, 96%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]1[CH2:15][CH:14]2[CH:12]([C:13]2([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[CH3:16])[C:11]1=O)[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([N:10]1[CH2:11][CH:12]2[CH:14]([C:13]2([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[NH2:23])[CH3:16])[CH2:15]1)[CH:8]=[CH2:9]
Reactant: C=CCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN1CC2C(C1)C2(C)c1cccc(N)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To dry tetrahydrofuran (300 ml) under nitrogen was added dropwise lithium aluminium hydride (1M in tetrahydrofuran, 75 ml, 75 mmol). To this solution, 3-allyl-6-(3-aminophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 51, 9.0 g, 37.1 mmol) dissolved in tetrahydrofuran (200 ml), was added dropwise at 0° C. The reaction mixture was stirred for 1 h and then heated to 50° C. for 3 h. The reaction mixture was quenched with water (150 ml) and solid sodium hydrogen carbonate was added. The slurry was extracted with ethyl acetate and then dichloromethane. The organic extracts were combined and dried (Na2SO4) and then concentrated in vacuo to give the title compound as a thick yellow oil (8.5 g, 100%).
Reaction SMILES: O[CH:2]1[C:10]2[N:6]([C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:8]3[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH3:18])[C:9]3=2)[C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.[CH3:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1>C(#N)C.[Au](Cl)(Cl)Cl>[CH3:18][N:11]1[C:9]2=[C:10]3[N:6]([C:7]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:8]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]1=[O:17])[C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH:2]3[C:32]1[O:31][C:30]([CH3:29])=[CH:34][CH:33]=1
Reactant: Cc1ccco1
Reactant: COC(=O)[C@@H]1CCC(O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1CCC(c2ccc(C)o2)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Gold (III) chloride (0.142 g, 0.469 mmol) was added to a solution of (7S)-methyl 10-hydroxy-1,3-dimethyl-2,4-dioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylate (1.8 g, 4.69 mmol) and 2-methylfuran (0.466 mL, 5.16 mmol) in acetonitrile (30 mL). The mixture was stirred at room temperature for 25 mins, then quenched with saturated NaHCO3(aq). The mixture was extracted with DCM, the organic phase passed through a hydrophobic frit and evaporated under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[CH3:20])=[CH:11][CH:12]=2)=[C:4]([CH3:21])[CH:3]=1.Br.C1C2C(=CC=CC=2)C=CC=1CS[C:35](=[NH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl>>[C:35]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[NH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:3][C:4]=3[CH3:21])=[CH:12][CH:11]=2)=[C:14]([CH3:20])[CH:15]=1)(=[NH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N=C(SCc1ccc2ccccc2c1)c1ccccc1
Reactant: Cc1cc(N)ccc1-c1ccc(-c2ccc(N)cc2C)o1
Agent: Br
Agent: Cl
Product: Cc1cc(NC(=N)c2ccccc2)ccc1-c1ccc(-c2ccc(NC(=N)c3ccccc3)cc2C)o1
Yield: 60 %

Procedure:
2,5-Bis[4-(benzimidoyl)amino-2-methylphenyl]furan (4e, DB626) was prepared according to the procedure for 4f using diamine 3b and S-(2-naphthylmethyl)-thiobezimidate hydrobromide as starting materials. Free base: yellow crystalline solid. Yield: 60%. 1H NMR (DMSO-d6): 2.48 (s, 6H), 6.50 (br s, 4NH), 6.75 (s, 2H), 6.84 (s, 4H), 7.44 (m, 6H), 7.71 (d, 2H), 7.95 (d, 4H). Hydrochloride: orange/yellow hygroscopic solid. 1H NMR (DMSO-d6): 2.61 (s, 6H), 7.03 (s, 2H), 7.38-7.44 (m, 4H), 7.63-7.68 (m, 4H), 7.75-7.80 (m, 2H), 7.94 (d, 6H). MS (EI): m/z 484 (M+, 100), 3.81 (87.2), 278 (37.9), 235 (5.4), 218 (3.1), 190 (5.5), 144 (11.1), 103 (32.8), 76 (9.3). Anal. Calcd. for C32H28N4O.2HCl.0.66H2O (569.39): C, H, N.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44]([C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1)=[O:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:49]([C:46]4([C:44](=[O:45])[NH:43][C:37]5[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=5[F:35])[CH2:48][CH2:47]4)=[O:50])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4F)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (400 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acid (241 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (116.2 mg).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>COCCOC>[CH3:18][N:19]([CH3:23])[C:20]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:21]
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: CN(C)C(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1=NC(=NOC(=O)N(C)C)SC1(C)C

Procedure:
15.8 g. (0.1 mol) of 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime and 15.2 g. (0.15 mol) of triethylamine were dissolved in 100 ml. of anhydrous 1,2-dimethoxy-ethane. 16.1 g. (0.15 mol) of dimethylcarbamoyl chloride were added dropwise. The mixture was refluxed for 3 hours and the solvent was distilled off under vacuum. The residue was dissolved in 100 ml. of dichloromethane and washed with water. After the organic phase was dried over sodium sulfate, the solvent was distilled off. The residue was purified chromatographically on silica gel using ether/dichloromethane (9:1) for the elution to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(dimethylcarbamoyl)-oxime, m.p. 108°-110° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)cc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:19]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:22]1[CH2:23][CH2:24][N:19]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:20][CH2:21]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5cccnc45)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 8-piperazin-1-yl-quinoline using a procedure similar to Example A1′. MS: APCI: M+1: 450.2 (Exact Mass: 449.22).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:15]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (500 mg, 2.35 mmol), 2-diethylaminoethylamine (300 mg, 0.363 mL, 2.59 mmol) and triethylamine (262 mg, 0.359 mL, 2.59 mmol) in CH2Cl2 (7 mL) was stirred at room temperature for 18 hours. The mixture is then diluted with dichloromethane, and washed with brine. The organic layers is dried (MgSO4) and the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[NH2:24]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:23]([NH:24][C:11](=[O:12])[C:10]2[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[CH:22]=[C:21]([O:20][CH3:19])[CH:27]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cc(N)cc(OC)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2c(F)cccc2F)cc(OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
5.5 ml (39.2 mmol; 1.2 equivalent) of triethylamine and 4.5 ml (35.9 mmol; 1.1 equivalent) of 2,6-difluorobenzoyl chloride are added to 5 g (32.6 mmol) of 3,5-dimethoxyaniline in solution in 100 ml of anhydrous toluene. The reaction medium is maintained under stirring at 70° C. for 1 hour 30 minutes, then, after returning to ambient temperature, washed with 3 times 50 ml of water. The resulting organic phase is dried over magnesium sulphate then the solvent is evaporated off under reduced pressure. The expected product is obtained in the form of a white powder (8.75 g; yield=97%) used in the following stage without other purification.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5](=[O:24])[CH2:6][C:7]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(O)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>O1CCCC1>[CH:18]1([C:7]2([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[O:25][C:3](=[O:2])[CH:4]=[C:5]([OH:24])[CH2:6]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)CC(=O)CC(O)(CCc1ccc(O)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-cyclohexyl-5-hydroxy-7-(4-hydroxy-phenyl)-3-oxo-heptanoic acid methyl ester (prepared in the previous paragraph) was dissolved in tetrahydrofuran (100 mL) and treated with 0.2N NaOH (900 mL) as described in General Method 7. The reaction was stirred for 3 hours at room temperature and then worked up as usual. The organic extracts obtained were combined, dried (MgSO4) and concentrated. Purification was accomplished by flash chromatography using CH2Cl2 :MeOH (99:1 to 98:2) to give the desired product as a solid, m.p. 52-58° C. 1H NMR (CDCl3) δ 1.0-1.9 (m, 12 H), 1.9-2.1 (m, 1 H), 2.5-2.7 (m, 3 H), 2.8 (d, 1 H), 3.4 (s, 2 H), 6.75 (d, 2 H), 7.05 (d, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:29].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:29]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Nc1cccc2c1CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3CCC4=O)c2cc1OC
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 4-amino-1-indanone (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.6 ml) was heated at 100° C. for 1 h 45 min. After cooling, the mixture was diluted with water and made alkaline with saturated NaHCO3. The precipitate was collected by filtration, washed with water and dried to give title compound (59 mg, 90%).
Reaction SMILES: [CH:1]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:2]=1[C:3]1[C:11]([CH:12]=[CH:13]2)=[C:10]([CH:18]=O)[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH3:26][C:21]([NH:20][CH2:18][C:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=[C:3]2[C:11]=1[CH:12]=[CH:13][C:14]1[C:2]2=[CH:1][CH:17]=[CH:16][CH:15]=1)([CH2:24][OH:25])[CH2:22][OH:23]
Reactant: O=Cc1c2ccc3ccccc3c2cc2ccsc12
Reactant: CC(N)(CO)CO
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccc3ccccc3c2cc2ccsc12
Yield: 71.2 %

Procedure:
Using the procedure outlined in Example 1, phenanthro[2,3-b]thiophene-7-carbaldehyde (24A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 71.2% yield of 2-methyl-2-[[(phenanthro[2,3-b]thiophen-7-yl)methyl]amino]-1,3-propanediol methanesulsonate, mp 212°-215° (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:5][CH2:6][O:7][C:8]1[NH:9][CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1.[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:31][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([F:1])[C:19]=1[O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)[CH2:5][CH2:6][O:7][C:8]1[N:9]([CH3:32])[CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To the solution of 2-(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethoxy)-5-ethylpyrimidin-4(1H)-one (30 mg, 0.068 mmol) and DIPEA (0.03 ml, 0.172 mmol) in DCM (1.5 ml) was added MeI (0.025 ml, 0.407 mmol). The solution was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (12 mg, 0.026 mmol, 38.8% yield). LCMS: rt=3.10 min, [M+H]=457
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH:14]2[CH2:19][CH:18]([C:20](=[O:56])[NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:26]=[C:25]4[C:50]3[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=3)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C([SiH](CC)CC)C>[C:8]1([CH:14]2[CH2:15][NH:16][CH2:17][CH:18]([C:20]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][N:26]=[C:25]4[C:50]3[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=3)=[O:56])[CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CNCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 3-phenyl-5-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-ylcarbamoyl)piperidine-1-carboxylate (0.117 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (1 drop) was added to the reaction and stirred for an additional 5 minutes. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:18]([F:23])[F:22])=[N:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccc(=O)[nH]c1)c1cccc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=C(c1ccc(OC(F)F)nc1)c1cccc(Br)c1
Temperature: 100 °C

Procedure:
The 5-[1-(3-bromo-phenyl)-vinyl]-1H-pyridin-2-one (10 g, 1 eq) was dissolved in acetonitrile (180 ml) and degassed for 1 hour. Then sodium chlorodifluoroacetate (8.5 g, 1.2 eq) was added and the mixture heated to 100° C. overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, the solvent was removed, and the crude was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried over sodium sulphate, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate. The 5-[1-(3-bromo-phenyl)-vinyl]-2-difluoromethoxy-pyridine was obtained as colorless oil (2.6 g, 26% of theory). MS (ISP): m/z=328 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[Cl:12].[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([Cl:12])=[CH:6][C:7]([NH2:11])=[C:8]([Br:14])[C:9]=1[Cl:10]
Reactant: [Br-]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(N)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.4 %

Procedure:
To a solution of 2,6-dichloro-4-aminobenzoic acid methyl ester (2.80 g) in CH2Cl2 (20 mL) at −10° C. was added a solution of tetrabutylammonium tribromide (6.94 g) in CH2Cl2 (30 mL) dropwise at −10° C. After 2 h, the mixture was warmed to room temperature, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4) to yield 2,6-dichloro-3-bromo-4-aminobenzoic acid methyl ester (2.99 g) ESMS: m/z 298 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:8][C:9](=[O:29])[CH:10]([NH:19][C:20](OC1C=CC=CC=1)=[O:21])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH:4]([N:8]1[C:9](=[O:29])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:19][C:20]1=[O:21])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)Oc1ccccc1)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C(C)C)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of the compound obtained in step c above (1140 mg) in DMF (14 mL) was added DIEA (0.6 mL, 3.30 mmol). After stirring overnight at room temperature, the solvent was removed. The residue was diluted with EtOAc and washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colourless oil (672 mg, 77%).