Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N.CO>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methoxybenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.5 mg). MS m/z 359 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSCC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCSCc1cccc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.05 g of the compound from Example 33A with a purity of 84% (2.19 mmol) in 20 ml of tetrahydrofuran was added dropwise to 9.1 ml (9.1 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran under argon in 50 ml of tetrahydrofuran at RT. The mixture was stirred at RT for 15 min and then, while cooling in ice, 1N hydrochloric acid was added. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 0.95 g (94% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:24]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)#[N:25]
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2C#N)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of methyl 4-(1-bromo-6-methoxynaphthalen-2-yl)benzoate (300 mg, 0.811 mmol) (see Example 12 step 1) in DMF (10 mL) was added Zn(CN)2 (191 mg, 1.62 mmol) and Pd(PPh3)4 (93.8 mg, 0.0811 mmol). The resulting mixture was stirred at 120° C. under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (60 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column (PE/EtOAc=200/1 to 50/1) gave the product (210 mg, yield 82%) as a solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([O:53][CH3:54])[CH:52]=1)[C:47]([OH:49])=O>>[F:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([O:53][CH3:54])[CH:52]=1)[C:47](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:49]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: COc1cc(F)cc(C(=O)O)c1
Product: COc1cc(F)cc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c1

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-fluoro-5-methoxybenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]-pyridin-2(3H)-ylidene)-5-methoxybenzamide (43.8% yield). MS m/z=581.4 [M+H], calc 580.69 for C31H41FN6O4.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22](C)[CH3:23])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CNC)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][NH:22][CH3:23])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
Following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (9) of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)quinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ7.95 (s, 1H), 7.74 (d, 1H), 7.65-7.55 (m, 3H), 7.35-7.28 (m, 2H), 5.22 (s, 1H), 4.51 (s, 2H), 2.88 (s, 3H), 2.67 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27ClN2O3: 427.9. Found: 427.2, 429.2.
Reaction SMILES: [CH:1]1CCCC=1.C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Ba+2].[C:18]([CH:22]1[C:26](=[O:27])[CH2:25][CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH:23]1[CH2:32][C:33]([OH:35])=[O:34])([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:1][O:34][C:33](=[O:35])[CH2:32][CH:23]1[CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH2:25][C:26](=[O:27])[CH:22]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C1C(=O)CC(OC(C)=O)C1CC(=O)O
Reactant: C1=CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1C(OC(C)=O)CC(=O)C1C(=O)OC

Procedure:
The cyclopentene acid, V, (9.5 g.) is dissolved in 180 ml. of benzene and the solution is hydrogenated at room temperature and atmospheric pressure in the presence of 0.5 g. of palladiated barium sulfate. When the theoretical amount of hydrogen is absorbed, catalyst is filtered off and the solution is evaporated to dryness under vacuum, yielding 9 g. (95%) of the methy ester of 2-carbomethoxy-3-oxo-5-acetoxycyclopentaneacetic acid with the required stereochemical configuration. The compound is a rather unstable solid, melting at 54° C; [α]d25 :- 17.8 (C=1.017% in CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].[C:13]([CH2:18][CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14].CCCCCCC>C1(C)C=CC=CC=1>[F:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][C:7]=1/[CH:8]=[C:18](\[CH3:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Yield: 79132.3 %

Procedure:
Compound 14b (14.6 mg) was dissolved in toluene (132 ml), and (carbetoxyethylidene)triphenylphosphorane (46.9 g) was added thereto. The obtained mixture was stirred under heating at 120° C. for 2 hours. After the reaction mixture was allowed to cool, n-heptane was added thereto and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (125 ml), and purified water was added thereto. The precipitated solid was filtered off and then dried under reduced pressure. Thus, Compound 14c (17.3 g, 79%) was obtained as an opalescent solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1ccc(OCCN2CCOCC2)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 4-iodophenol 99b (2.50 g, 11.4 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.14 g, 11.5 mmol), potassium carbonate (7.88 g, 57.0 mmol), and acetonitrile (50 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at 85° C. for 20 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a pale orange oil. This oil was purified via column chromatography (eluting with 0-100% ethyl acetate-hexane) to afford 4-[2-(4-iodo-phenoxy)-ethyl]-morpholine 100b as a pale yellow oil. MS (MH+) 334.0; Calculated 333 for C12H16INO2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[CH2:6][CH2:5]2.Cl>C(O)C.CCOCC>[ClH:1].[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1N1CCc2cc(Cl)ccc21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccccc1N1CCc2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A mixture of 13.7 g of 5-chloro-1-(2-nitrophenyl)indoline and 0.25 g of 1% Pt on C in 250 ml absolute ethanol is shaken at 50 psi of H2 until the theoretical amount of H2 is taken up. The mixture is filtered and the solvent removed at 50° C. to leave the product base as an oil. This is dissolved in 200 ml of ether, cooled to 0° C., and treated with gaseous HCl to precipitate 1-(2-aminophenyl)-5-chloroindoline hydrochloride, m.p. 235°-238° C. dec.
Reaction SMILES: C1COCC1.C(O)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([NH:22][C:23](=[O:32])[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=1.[BH4-].[Na+]>C(OCC)(=O)C>[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23](=[O:32])[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: COC(=O)c1cc(NC(=O)CSc2ccccc2)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CSc1ccccc1)Nc1cc(CO)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a THF/ethanol(10:1) solution of 3-(2-Phenylsulfanyl-acetylamino)-5-trifluoromethyl-benzoic acid methyl ester (252 mg, 0.68 mmol) was added sodium borohydride (46 mg, 1.4 mmol), and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was left overnight. The mixture was diluted with ethyl acetate, washed with 1 N HCl (2×) and brine. The organic layer was dried over MgSO4, filtered and stripped. The crude product was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate (4:1) to give 126 mg of N-(3-Hydroxymethyl-5-trifluoromethyl-phenyl)-2-phenylsulfanyl-acetamide in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1.C(O)C>[Pt](=O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Platinum(IV) oxide (0.107 g) was added to the suspension of tert-butyl 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.05 g; 3.15 mmol) in the mixture of ethanol (20 mL) and acetic acid (10 mL). After degassing, the mixture was subjected to hydrogenation for 20 hours and was filtered through celite. The filtrate was concentrated under reduced pressure to give 1.03 g (98%) of tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate as a solid.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:41]([NH2:44])([CH3:43])[CH3:42])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:41]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:42])[CH3:43])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(C(C)(C)N)cc1OC
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1OC
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(3,4-dimethoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10e) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 60%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[N:12]([O-])=O.[Na+].[OH-].[NH4+]>Cl.O>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:12]=[C:9]2[C:10]#[N:11]
Reactant: O=N[O-]
Reactant: N#CCc1cc(Br)ccc1N
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: N#Cc1n[nH]c2ccc(Br)cc12
Temperature: -50 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a cooled solution of (2-amino-5-bromophenyl)acetonitrile (11 g, 52 mmol) in concentrated hydrochloric acid (110 mL) at −50° C., a solution of sodium nitrite (3.9 g, 57 mmol) in water (20 mL) was added slowly. After the addition, the mixture was stirred at −50° C. for 2 h. The mixture was neutralized with 33% ammonium hydroxide at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford 5-bromo-3-cyanoindazole (7 g, 60%) as a solid. 1HNMR (CDCl3) δ ppm 10.7 (br, 1H), 8.1 (s, 1H), 7.84 (d, 1H), 7.5 (d, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][C:11]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])([CH3:13])[CH3:12]>C1COCC1.C(OCC)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][OH:8])[CH:19]=1
Reactant: COC(=O)CC(C)(C)c1cc(F)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CCO

Procedure:
To a suspension of LAH (1.64 g) in 100 mL of THF stirred under argon was added dropwise over 30 minutes a solution of the above 3-(5-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester in 10 mL of THF (vigorous reaction). The mixture was stirred at room temperature overnight. The reaction was diluted with 200 mL of diethyl ether and quenched by the addition of 3 mL of water (added cautiously) and 3 mL of acetic acid. The mixture was filtered through diatomaceous earth and washed through with diethyl ether. Evaporation of the solvent gave 10.8 g of 3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol, which was used without additional purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([O:30][CH2:31][O:32][CH3:33])=[C:14]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][O:28][CH3:29])[OH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl.CCOCC>[Cl:11][C:12]1[C:13]([O:30][CH2:31][O:32][CH3:33])=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][O:28][CH3:29])=[O:19]
Reactant: COCOc1ccccc1C(O)c1cccc(Cl)c1OCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCOc1ccccc1C(=O)c1cccc(Cl)c1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A solution of 16.0 ml of oxalyl chloride in 500 ml of dichloromethane was placed in a 1 l flask and cooled with a dry ice-acetone bath. Dimethyl sulfoxide (14.0 ml) was added dropwise with stirring over a 10 min period. After a 40 min reaction period, a solution of 51.0 g of (3-chloro-2-methoxymethoxyphenyl)(2-methoxymethoxyphenyl)methanol in 120 ml of dichloromethane was added dropwise over a 45 min period with stirring at about -78° C. and allowed to react another 45 min. An orange suspension formed. Triethylamine (50 ml) was added and the slurry was swirled occasionally and was allowed to warm to room temperature. The slurry was diluted with 1 l of ether and the resulting mixture was extracted with 3-300 ml portions of water, 300 ml of 2 percent hydrochloric acid, and 200 ml of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 50.5 g of the title compound as a viscous pale orange-tinted oil. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH2:7])=[S:6])[CH2:3][CH2:2]1.[C:8](#[N:12])[CH2:9][C:10]#[N:11]>>[CH:1]1([N:4]2[C:10]([NH2:11])=[CH:9][C:8]([NH2:12])=[N:7][C:5]2=[S:6])[CH2:3][CH2:2]1
Reactant: N#CCC#N
Reactant: NC(=S)NC1CC1
Product: Nc1cc(N)n(C2CC2)c(=S)n1
Yield: 38 %

Procedure:
N-cyclopropylthiourea (6.2 g) and malononitrile (6.6 g) were reacted in the same method as described in Preparation 12 to give the pale yellow above-indicated compound(3.7 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:18][CH2:17][CH:16]=[CH:15]1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]([NH2:22])=[N:19][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([CH:14]2[CH2:18][CH2:17][CH:16]=[CH:15]2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)ccc1C1C=CCC1
Reactant: N=C(N)N
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1C1C=CCC1

Procedure:
Analogously to Example 1, by reaction of 2.2 g of 3-methylsulfonyl-4-(1-cyclopenten-3-yl)-benzoyl chloride with guanidine, customary working up gives N-diaminomethylene-3-methylsulfonyl-4-(1-cyclopenten-3-yl)benzamide, which can be recrystallized from acetonitrile/diethylether, m.p. 188°-190°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30].C(N(CC)C(C)C)(C)C.C(#N)C>CCOC(C)=O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 57.5 %

Procedure:
A mixture of N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (1.0 g, 3.2 mmol), 5-bromo-2-fluorobenzonitrile (0.97 g, 4.8 mmol), N,N-diisopropylethylamine (1.7 mL, 9.7 mmol), and acetonitrile (10 mL) was subjected to microwave irradiation at 180° C. for 2 h. More 5-bromo-2-fluorobenzonitrile (1.0 g) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. Then additional 5-bromo-2-fluorobenzonitrile (1.0 g) was added and the reaction mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. After cooling, the mixture was diluted with EtOAc (100 mL) and washed with aq. Na2CO3 solution and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column (100% EtOAc) to yield a light yellow solid (0.90 g, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.CC(C)([O-])C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:67][C:68]1[CH:73]=[CH:72][C:71]([S:74]([NH:77][CH3:78])(=[O:76])=[O:75])=[CH:70][CH:69]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:14][C:4]1[N:3]=[C:2]([NH:67][C:68]2[CH:73]=[CH:72][C:71]([S:74]([NH:77][CH3:78])(=[O:76])=[O:75])=[CH:70][CH:69]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1cc(N2CCCCC2)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of 2′,6′-dichloro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl (500 mg, 2.15 mmol) in toluene (6 mL) were added potassium tert-butoxide (486 mg, 4.3 mmol), palladium(II) acetate (24 mg, 0.1 mmol), BINAP (67 mg, 0.1 mmol), and 4-amino-N-methylbenzenesulfonamide (444 mg, 2.15 mmol) were taken in a 10 mL reaction vessel. This reaction mixture was subjected the microwave irradiation, in which the microwave power was 250 W, to attain a reaction temperature of 1 50° C. After this reaction proceeded for 30 min, water (200 mL) was added to the reaction mixture and the reaction product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate concentrated under vacuum. The product was purified through column chromatography using 230-400 mesh silica gel to afford the desired compound as light yellow solid (290 mg, yield, 35%).