Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([O:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:13]=[N:12]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=c1cc(OCC2CCCC2)cn[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
A solution of 5-cyclopentylmethoxy-2H-pyridazin-3-one (494.8 mg, 2.54 mmol) in tetrahydrofuran (12 mL, 0.21 M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 0.67 g, 2.84 mmol). The reaction was then warmed to 50° C., where it stirred overnight. The reaction sat at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×75 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 10-30% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (713.9 mg, 80%) as a clear light yellow oil; ES+-HRMS m/e calcd for C19H28N2O4 [M+H+] 349.2122, found 349.2120. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (m, 2H), 1.23-1.82 (m, 15H), 1.87-1.98 (m, 1H), 2.05-2.23 (m, 1H), 2.23-2.37 (m, 1H), 3.61 (s, 3H), 3.91 (d, J=7.0 Hz, 2H), 5.39 (dd, J=10.9, 4.3 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 7.83 (d, J=2.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][C:20]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:34][CH:35]=4)[N:3]=[C:4]([NH:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]4)[C:5]=3[N:11]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4(C(F)(F)F)CC4)c3n2)cc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CC3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Temperature: 140 °C
Yield: 50.1 %

Procedure:
A mixture of [2-Chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-(1-trifluoromethyl-cyclopropyl)-amine (51.6 mg) and 4-aminomethyl-benzenesulfonamide hydrochloride (51.4 mg) was dissolved in NMP (1 mL) and treated with diisopropylethylamine (0.065 mL). The reaction mixture was sealed and heated by microwave to 140° C. for 1.5 h. The reaction mixture was cooled and purified by preparative HPLC (5-95% acetonitrile:water with 0.1% TFA) to afford 36 mg (41% yield) of the title compound as its TFA which was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 1.26 (br s, 2H), 1.37 (br s, 2H), 4.80 (d, 2H), 7.34-7.40 (m, 4H), 7.55 (d, 2H), 7.78 (d, 2H), 7.99 (d, 1H), 8.48 (m, 3H), 8.9 (br s, 1H), 10.1 (br s, 1H); MS (m/z): 533.2 ([M+H]+, 100).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@H](CCl)CN1c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 92.2 %

Procedure:
A mixture of (5S)-5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.44 g, INTERMEDIATE 6) and sodium azide (1.28 g) was heated to 100° C. in 80 ml of dimethylformamide for 15 h. The mixture was then diluted with 500 ml of water and extracted with 500 ml of ethyl acetate (3×). The combined organic layers were washed with water (250 ml) and brine (250 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 2.31 g (92%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]1(=[O:41])[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][O:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH:36]6[CH2:35][O:34][C:33](=[O:41])[CH:37]6[CH2:38]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: O=C1OCC2CNCC12
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC3COC(=O)C3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-hexahydro-furo[3,4-c]pyrrol-1-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and hexahydro-furo[3,4-c]pyrrol-1-one following General Procedure B.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C@@H:28]5[CH2:29][O:30][CH2:31][CH2:32][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1COCCO1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (22 mg, 19%), MS (ISP) m/z=457.4 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (R)-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[Na+:27].[Na+]>>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([O-:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([O-:22])=[O:21].[Na+:27].[Na+:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C([O-])c1ccc2c(c1)C(=O)c1ccc(C(=O)[O-])cc1C2=O

Procedure:
Anthraquinone-2,6-dicarboxylic acid (0.50g) was dissolved in sodium carbonate solution (1 equivalent of sodium carbonate, 0.18g, in water, 100 ml) with warming. As the di-sodium salt did not separate on cooling, the solution was evaporated to approximately 1/3 volume and heavily diluted with ethanol. The solid which separated was filtered off, dried at 100°C. and analysed for the dihydrate. Analysis:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:30]1[CH2:35][CH2:34][CH2:33][C@H:32]([C:36]#[N:37])[CH2:31]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:36]([C@H:32]1[CH2:33][CH2:34][CH2:35][C@H:30]([O:8][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31]1)#[N:37]
Reactant: N#C[C@H]1CCC[C@@H](O)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C[C@H]1CCC[C@H](OC(=O)c2ccccc2)C1
Reaction time: 12 h
Yield: 14.4 %

Procedure:
To a solution of benzoic acid (1.1 g, 8.8 mmol) and PS-triphenylphosphine (6.7 g, 15.5 mmol) in anhydrous THF (40 mL) was added cis-3-hydroxy-cyclohexanecarbonitrile (1.1 g, 8.8 mmol) in anhydrous THF (20 mL). The reaction mixture was cooled while diethyl azodicarboxylate (DEAD) (1.9 mL, 12.3 mmol) was added by syringe over 3 min. The reaction was shaken for 12 h. The mixture was filtered and the resin was washed with ether. The filtrate was concentrated in vacuo to afford an oily solid. Silica gel column chromatography using 95:5 hexanes:EtOAc as an eluent afforded 0.29 g (14%) of benzoic acid trans-3-cyano-cyclohexyl ester as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1>C(OCC)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[NH:26][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)[nH]c2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-fluoro-benzyl)-piperidine-1-yl]-ethanone and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 142b. Melting Point: 249-251° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (80 mg, 0.1886 mmol), 4-dimethylaminopyridine (12 mg, 0.0983 mmol) and morpholine (33 mg, 0.3793 mmol) were dissolved in methylene chloride (10 ml), WSC-HCl (109 mg, 0.5685 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (51 mg, 0.1036 mmol, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:22][CH2:23][CH:24]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]1=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Reactant: CCCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(CC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one (0.15 g, 0.51 mmol) from Example 6 in 1 mL of dichloromethane and 0.5 mL of acetic acid was treated with 3-hexanone (0.3 g, 3 mmol) and sodium cyanoborohydride (0.1 g, 1.6 mmol). The resulting mixture was stirred at ambient temperature for 6 h after which time additional 3-hexanone (0.1 g, 1 mmol), sodium cyanoborohydride (0.05 g, 0.8 mmol) and methanol (0.5 mL) were added. Stirring was continued for 12 h. A third portion of 3-hexanone (0.17 g, 1.7 mmol) and sodium cyanoborohydride (0.055 g, 0.9 mmol) was added and stirring continued for an additional 16 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). The combined extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.175 g (90%) of 1-[2-(3-hexylamino)-4-methoxycarbonylphenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:16]1
Reactant: OB(O)c1cccc2ncccc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2cccc3ncccc23)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using quinolin-5-ylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(quinolin-5-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 7.43-7.51 (m, 3 H) 7.64-7.68 (m, 1 H) 7.82-7.89 (m, 2 H) 8.01-8.05 (m, 2 H) 8.20 (s, 1 H) 8.33 (d, J=8.02 Hz, 1 H) 8.93 (dd, J=4.12, 1.60 Hz, 1 H). m/z (ESI) 421.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[C:15]([OH:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.N1C=CC=CC=1>C(OCC)(=O)C>[OH:5][C:6]1[C:15]([O:16][C:1](=[O:3])[CH3:2])=[CH:14][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)Cl
Reactant: Oc1cc2ccccc2cc1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc2ccccc2cc1O
Temperature: 25 °C

Procedure:
Acetylchloride (0.71 ml) was added to a solution of 2,3-dihydroxynaphthalene (1.6 g) and pyridine (0.81 ml) in ethyl acetate (20 ml) at 0° C. The mixture was stirred for few hours at room temperature and then washed with water, dried and evaporated to dryness. The crude product was recrystallized from ether. Yield: 0.52 g.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.075 g, 0.746 mmol) obtained in step 4 and methanesulfonamide (0.071 g, 0.749 mmol), the title compound (0.026 g, 30%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)(C)C>[ClH:1].[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(c1C)NCC2
Reactant: Clc1ncnc2cnccc12
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1C)N(c1ncnc3cnccc13)CC2
Product: Cl
Yield: 15.9 %

Procedure:
To 4-chloro-pyrido[3,4-d]pyrimidine (200 mg, 1.21 mmol) in isopropanol (3 mL) was added 6,7-dimethylindoline (211 mg, 1.44 mmol) and pyridine (190 mg, 2.41 mmol). The reaction mixture was heated to reflux under an atmosphere of dry nitrogen for 6 hours. Solvent was removed in vacuo and the residue was dissolved in CHCl3 and washed with saturated aqueous sodium carbonate. The organic phase was dried over sodium sulfate concentrated in vacuo, and flash chromatographed on silica in 45% acetone/hexanes to afford 60 mg of the free base of the title product (LC-MS: 278 (MH+). This material was dissolved in a minimum volume of 10% methanol in methylene chloride and 1 mole equivalent of HCl in ether was added dropwise with stirring. The reaction mixture was diluted with four volumes of ether and the precipitated title product was filtered and dried in vacuo (58 mg; M.P. 248° C.; GC-MS: 277 (M+); anal. RP-HPLC:4.06 min.)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([NH2:30])=[N:22]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:8]1([C:6]2[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:30][C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][N:22]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1-c1nc(Nc2n[nH]c3ccccc23)cc(C2CC2)n1
Temperature: 165 °C
Yield: 15.9 %

Procedure:
A mixture of 4-chloro-6-cyclopropyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.08 g, 0.27 mmol) and 1H-indazol-3-ylamine (0.036 g, 0.41 mmol) was heated neat at 160-170° C. for 6 hours. The residue was cooled and dissolved in N-methyl-pyrrolidinone (2 mL), poured into water (30 mL) and sodium bicarbonate (5 mL) then filtered, washing with water and ether. The collected precipitate and the ether wash were combined and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.017 g, 15% yield) as a pale yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.6 (br s, 1H), 10.2 (br s, 1H), 8.00 (d, J=8.1 Hz, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.71 (m, 3H), 7.65 (t, J=7.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 2.04 (m, 1H), 1.01 (m, 2H), 0.96 (m, 2H) ppm; LC-MS 396.10 (M+H); Rt (Method A) 3.122 minutes.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].O>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) in methanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (102 mg, 0.601 mmol) and the reaction was heated to reflux for 2 minutes. After cooling back to the room temperature, sodium cyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixture and was stirred for 1 hour. Water (20 mL) was added. The reaction was concentrated and 20 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, and dried over MgSO4, filtered and evaporated. The resulting oil was purified on preparatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier). 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-Methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (95 mg, 0.250 mmol, 41.7% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz, 1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz, 1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H), 1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m, 1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83 min; MS (ESI): 288.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](O)(=[O:25])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1>ClCCl>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred solution of N1-(4-(phenylthio)pyrimidin-2-yl)benzene-1,3-diamine (80 mg, 0.27 mmol) and acrylic acid (37 μL, 0.54 mmol) in anhydrous dichloromethane (2 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride salt (78 mg, 0.41 mmol), triethylamine (114 μL, 0.82 mmol) and 4-pyrrolidinopyridine (5 mg). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. It was diluted with dichloromethane (20 mL), washed with water, 2.0 M aqueous sodium carbonate solution, and dried (Na2SO4). After removal of the solvent in vacuo, the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (50:50→100:0) as eluant to give the desired product (31 mg, 33%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[C:6]([C:9]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:10]=1[O:11][CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])(=[O:8])[CH3:7].[CH3:30][CH2:31][O:32]CC>C(OCC)(=O)C(OCC)=O.C(O)C.Cl>[C:2]([C:3]1[O:29][C:28]2[C:9]([C:6](=[O:8])[CH:7]=1)=[C:10]([O:11][CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[CH:25]=[CH:26][CH:27]=2)([O:32][CH2:31][CH3:30])=[O:1]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1cc(C)ccc1C
Reactant: CC[O-]
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cc(C)ccc3C)cccc2o1

Procedure:
To a suspension of sodium ethoxide, prepared from sodium (3.0 g) and ethanol (30 ml), in dry ether (200 ml), was added a solution of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-(2,5-dimethylphenoxy) propane (13.2 g) in diethyl oxalate (15 ml). The resultant solution was heated under reflux for 2 hours, and then poured onto ice (100 g). After acidification with a solution of acetic acid (12 ml) in water (80 ml), the ether layer was separated, and the aqueous layer extracted with ether (3 × 25 ml). The combined ethereal extracts were evaporated under reduced pressure to give a yellow oil. This was dissolved in ethanol (96%, 100 ml) containing hydrochloric acid (10 drops) and heated under reflux for 1 hour. Removal of the ethanol under reduced pressure gave 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-(2,5-dimethylphenoxy) propane as a yellow gum (15.2 g) which could not be crystallized.