Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[Li+].[OH-].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(Cl)ccc1NN
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(4-chloro-2-methylphenyl)hydrazine as the hydrochloride salt (96 mg, 0.5 mmol) in Et2O (10 mL) was added a 2 N solution of LiOH (3 mL), and the resulting mixture was stirred for 15 minutes. After the system became homogenous, furan-2-carbonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The crude material of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide obtained after the removal of the solvent was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]=1[C:18]#[N:19].C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C.C1(C)C=CC=CC=1>C(O)C>[C:11]([NH:10][CH2:9][CH2:8][NH:7][C:4]1[C:3]([C:18]#[N:19])=[C:2]([N:1]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:6][N:5]=1)([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCNc1n[nH]c(N)c1C#N
Reactant: CCOC(OCC)N(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(NCCNC(=O)OC(C)(C)C)c1C#N
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 76.3 9 (286.1 mmol) of 5-amino-3-[2-(Boc-amino)-ethylamino]-4cyano-pyrazole, 54 ml (315.1 mmol) of N,N-dimethylformamide diethyl acetal, 850 ml of toluene and 85 ml of ethanol is stirred at 100° C. for 5 hours. A further 24.5 ml (143 mmol) of N,N-dimethylformamide diethyl acetal are then added to the reaction mixture and stirring is continued for a further 3 hours at 100° C. After cooling to about 10° C., filtration and washing the filter residue with toluene and diethyl ether, 3-[2-(Boc-amino)-ethylamino]-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole is obtained; m.p. 158-160° C.; ESI-MS: (M−H)−=320.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:23])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:23])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N)c1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NS(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cold mixture of 2-(3-amino-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (0.19 mmol, 1.0 eq.) in pyridine (5 mL) was added 3-fluorobenzene-1-sulfonyl chloride (0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to afford 2-(4-fluoro-3-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a pale yellow solid; Yield: 65%; MS (ESI+APCI) M+1=473.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[CH3:23][C:24]([CH3:39])([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N:18]([C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:24]([CH3:25])([CH3:23])[CH3:39])=[O:28])[CH2:30][CH2:31]4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Yield: 83.5 %

Procedure:
The title compound (563 mg) was prepared similarly from 1-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-piperazine (400 mg, 1.21 mmol) and 1-(1,1-dimethylethoxycarbonyl)-4-piperidine-acetic acid (589 mg, 2.42 mmol); MS (CI, M+H)=557; HRMS: calc.: 557.2353; found: 557.2351.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:13]2[C:12](=[O:24])[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4].[CH3:26][C:27]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:28]=1[O:29][CH2:30][CH:31]1[O:33][CH2:32]1>CO.Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:13]2[C:12](=[O:24])[CH2:11][N:10]([CH2:32][CH:31]([OH:33])[CH2:30][O:29][C:28]3[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:27]=3[CH3:26])[CH2:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4]
Reactant: Cc1cccc(OCC2CO2)c1C
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1c(F)ccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(CC(O)COc3cccc(C)c3C)C2)C1c1c(F)ccc(Cl)c1Cl
Yield: 16.7 %

Procedure:
4-(2,3-Dichloro-6-fluorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-1,7-naphthyridine-3-carboxylic acid methyl ester (12.1 g), 5.3 g of 3-(2,3-dimethylphenoxy)-1,2-epoxypropane and 150 ml of methanol were combined and refluxed for 18 hours. The alcohol was evaporated in vacuo. The residue was chromatographed on silica-gel using a 5% methanol-ethyl acetate system. The residue obtained on evaporation was dissolved in methanol and saturated with hydrogen chloride. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. A precipitate formed on standing at room temperature. The solid was separated and treated with boiling acetonitrile. The solid was dried in vacuo to obtain 2.8 g of the title compound as the hydrochloride salt, m.p. 190°-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Br)cc1
Yield: 100 %

Procedure:
A solution of 50.0 g (232 mmol) of 4-bromophenyl-acetic acid in 150 mL of thionyl chloride was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo to afford 54 g (100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)[CH2:11][CH3:12])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccc(F)cc1)C(=O)O
Product: CCC(Oc1ccc(F)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(4-fluorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CS(O[CH2:33][C:34]1([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35]1)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:33][C:34]1([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][CH2:36]1)[CH:6]=[C:5]2[S:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CSc2c[nH]c(=O)c3ccc(Br)cc23)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CSc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)C1
Yield: 40.3 %

Procedure:
tert-Butyl (3S)-3-{[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}-piperidine-1-carboxylate (Example 63c, 190 mg) was reacted with [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (136 mg) by the method of Example 58c to afford the subtitle compound (110 mg) as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([CH:17]([Cl:23])[CH2:18][CH2:19][N:20]=[C:21]=[O:22])C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:21]([NH:20][CH2:19][CH2:18][CH2:17][Cl:23])=[O:22])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: CCC(Cl)CCN=C=O
Product: COc1c(I)cc(NC(=O)NCCCCl)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 3-chloropropyl isocyanate (0.103 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound which was used without purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]([O:22][CH3:23])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>O1CCCC1>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([O:24][CH3:25])[C:12]([NH:11][CH:1]=[O:3])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC=O)c(OC)cc1OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 1.96 g portion of acetic anhydride was mixed with 0.89 ml of formic acid, followed by stirring at 50° C. for 2 hours. The resulting solution was mixed with 1.5 g of methyl 5-amino-2,4-dimethoxybenzoate dissolved in advance in 3 ml of tetrahydrofuran, followed by 6 hours stirring. After completion of the reaction, the thus precipitated product of interest was collected by filtration, washed with diethyl ether and then dried under a reduced pressure to give 1.62 g of methyl 2,4-dimethoxy-5-formylaminobenzoate.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Zn](CC)CC.C(I)I.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27](=[CH2:33])[CH2:26]1)[C:20]#[N:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27]2([CH2:1][CH2:33]2)[CH2:26]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1CC(c2ccc(C#N)cc2F)n2cncc21
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: N#Cc1ccc(C2CC3(CC3)c3cncn32)c(F)c1
Reaction time: 2 h

Procedure:
A solution of TFA (0.234 mL, 3 mmol) in 0.6 mL of dry CH2Cl2 is added dropwise to a solution of Et2Zn (1M in Hexanes, 3.06 mL, 3.06 mmol) at 0° C. The resulting suspension is subsequently treated with a solution of CH2I2 (0.246 mL, 3.06 mmol) in CH2Cl2 (0.4 mL). After 2 h at 0° C., a solution of 3-fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (333.8 mg, 1.392 mmol) in CH2Cl2 is added. After overnight, the reaction is quenched with saturated NaHCO3 solution, and extracted with CH2Cl2 (20 mL×4). The combined extracts are washed with brine, dried over anhydrous Na2SO4. After filtration and evaporation, the residue is purified by chromatography and yield 112 mg of oil. MS (ESI) m/z 254.2 (M+H). 1H NMR (400.3 MHz, CDCl3): δ 8.93 (s, 1H), 7.54-7.52 (m, 1H), 7.45 (d, J=8.00 Hz, 1H), 7.35 (m, 1H), 6.83 (s, 1H), 6.27 (brs, 1H), 3.22 (m, 1H), 2.61 (d, J=12 Hz, 1H), 1.33-1.19 (m, 2H), 1.16-1.14 (m, 1H), 0.90-0.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:20]1([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2cc(N3CCOCC3)ccc2C1
Yield: 49 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.305 mmol), morpholine (0.0292 ml, 0.335 mmol), X-phos (8.70 mg, 0.0182 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.52 mg, 0.00604 mmol) and sodium tert-butoxide (43.8 mg, 0.456 mmol) in dioxane (2 ml) was stirred under an argon atmosphere for 7 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (50.0 mg, 49.0%) as an oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH2:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:11]([C:13]1[C:21]2[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:13]3[C:21]4[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15][N:14]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Reactant: NCC12CCN(CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a stirred solution of quinuclidin-4-ylmethanamine (1.0 g, 7.14 mmol) in 1,4-dioxane (30 mL) was added methyl 3-formyl-1H-indazole-4-carboxylate (1.2 g, 6.0 mmol) in 1,4-dioxane (10 mL). Then glacial acetic acid (1% of total solvent used) was added and the reaction mixture was stirred at 60° C. for 2 h. It was cooled to room temperature and sodium triacetoxyborohydride (3.8 g, 17.9 mmol) was added. The reaction mixture was stirred at room temperature for 4 h). The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 70:27:3 dichloromethane/methanol/concentrated ammonium hydroxide) to give methyl 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate as a brown oil (2.1 g, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.87 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.38 (s, 2H), 3.99 (s, 3H), 3.27 (t, J=8.0 Hz, 6H), 2.68 (s, 2H), 1.78 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 329 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].[N+:36]([C:39]1[C:48]2[N:47]=[C:46]([C:49]([F:52])([F:51])[F:50])[O:45][C:44](=[O:53])[C:43]=2[CH:42]=[CH:41][CH:40]=1)([O-:38])=[O:37].[OH-].[Na+]>O1CCOCC1>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[NH:1][C:44](=[O:53])[C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([N+:36]([O-:38])=[O:37])[C:48]=1[NH:47][C:46](=[O:45])[C:49]([F:51])([F:52])[F:50])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]
Reactant: O=c1oc(C(F)(F)F)nc2c([N+](=O)[O-])cccc12
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 114.8 %

Procedure:
To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (6.0 g) in 1,4-dioxane (200 ml) was added 8-nitro-2-trifluoromethyl-3,1-benzoxazin-4-one (3.24 g) and the mixture was stirred at 100° C. for 4 hours. To the mixture was added 8-nitro-2-trifluoromethyl-3,1-benzoxazin-4-one (3.24 g). and the solution was stirred at 100° C. for additional 3 hours. To the mixture was added 1N sodium hydroxide solution (90 ml) and the resulting solution was stirred at 60° C. for 1 hour. After being concentrated in vacuo, the residue was diluted with chloroform and the organic solution was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and the solvent was concentrated in vacuo to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(3-nitro-2-trifluoroacetylaminobenzoyl)aminobenzamide as a yellow powder (10.6 g). The crude product was used for next step without further purification.
Reaction SMILES: [N:1]#[C:2]Cl.[CH3:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1>[OH-].[Na+]>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:2]#[N:1])[CH:6]=1
Reactant: Cc1cccnc1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Product: N#CCc1cccnc1

Procedure:
As the reactor there was used a quartz tube 1 meter long and 20 mm wide which was heated from the outside. There were fed into the tube separately from each other in homogeneous flow hourly 7.1 grams (0.12 mole) of cyanogen chloride and 42.8 grams (0.46 mole) of 3-methylpyridine) both of which were preheated to 550° C. The reaction temperature was 680° C. The reaction mixture was treated hourly with 1.2 liters of 5 percent aqueous sodium hydroxide solution in a gas washer directly post-connected to the reactor. The aqueous mixture which discharged from the gas washer was extracted hourly with 2 liters of dichloromethane. By distillation of the organic phase there were recovered the dichloromethane and the unreacted 3-methylpyridine. The pyridine-3-acetonitrile obtained had a boiling point of 101° to 109° C. at 1, 5 mbar. Its purity was 98 to 99%. The yield amounted to 10.4 grams, corresponding to 75% based on the cyanogen chloride added.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[OH-].[Na+]>CO>[F:32][C:2]([F:1])([F:31])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: COC(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Yield: 89.1 %

Procedure:
Methyl 3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylate (3.28 g, 7.38 mmol) and 2M NaOH (10 mL, 7.38 mmol) in methanol (80 mL) were heated under reflux for 40 hours. The resulting solution was concentrated by evaporation, then acidified to pH 2-3 with 2M hydrochloric acid to give a colourless precipitate. The precipitate was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to afford 3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylic acid (2.83 g, 89%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:53]=[CH:52][C:51]4[C:42](=[C:43]5[C:48](=[CH:49][CH:50]=4)[CH:47]=[CH:46][CH:45]=[N:44]5)[N:41]=3)=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:41]1[C:42]2[C:51](=[CH:50][CH:49]=[C:48]3[C:43]=2[N:44]=[CH:45][CH:46]=[CH:47]3)[CH:52]=[CH:53][C:40]=1[C:37]1[CH:38]=[CH:39][C:34]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:12]3[N:13]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[N:9]=[C:10]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:11]=3)[CH:19]=2)=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc4ccc5cccnc5c4n3)cc2)OC1(C)C
Reactant: Brc1cccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cccc(-c4ccc(-c5ccc6ccc7cccnc7c6n5)cc4)c3)n2)cc1
Temperature: 25 °C

Procedure:
In a stream of argon, 1.20 g of 2-(3-bromophenyl)-4,6-diphenyl-1,3,5-triazine, 1.30 g of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,10-phenanthroline, 1.11 g of cesium carbonate, 14 mg of palladium acetate and 32 mg of triphenylphosphine were suspended in 140 mL of tetrahydrofuran. The suspension was heated under reflux for 19 hours. Then the reaction mixture was left to be cooled to room temperature, and distilled under a reduced pressure to remove low-boiling point ingredients. Methanol was added to the residue. The thus-deposited solid was collected by filtration, and purified by silica gel column chromatography using a methanol/chloroform (1:100 to 1:77) mixed solvent as a developing solvent to give 1.37 g of target 2-[4′-(1,10-phenanthrolin-2-yl) biphenyl-3-yl]-4,6-diphenyl-1,3,5-triazine as a white solid (yield, 79%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of 1H-indole-5-carbaldehyde CCLXIII (2.00 g, 13.778 mmol, 1 eq.) in dichloromethane (40 mL) was added, at room temperature, tetrabutylammonium hydrogen sulfate (0.1 eq.) followed by a solution of sodium hydroxide (10.0 eq.) in water (20 mL). Phenylsulfonyl chloride (1.2 eq.) was then slowly added and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 20/80 to 35/65) to give 3.671 g (93% yield) of 1-benzenesulfonyl-1H-indole-5-carbaldehyde CCLXIV as a white solid.