Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:18][C:19](=[CH2:22])[CH:20]=[CH2:21]>ClCCl.[I-].[Zn+2].[I-]>[O:18]=[C:19]1[CH2:20][CH2:21][C:10]([NH:9][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:22]1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C(NC(=O)c1ccccc1)C(=O)OC
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the crude product (67.0 g) of methyl 2-[(phenylcarbonyl)amino]prop-2-enoate produced above in dichloromethane (300 mL) was added zinc iodide (104 g). To the mixture was added trimethyl[(1-methylideneprop-2-en-1-yl)oxy]silane (173 mL), and the mixture was heated under reflux for 24 hr. The reaction system was allowed to cool to room temperature, washed with water, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration. To the filtrate were added a mixture (1:4, 40 mL) of 1M hydrochloric acid and tetrahydrofuran, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (56.0 g).
Reaction SMILES: [CH3:1][N:2]([C:10]1(/[CH:13]=[CH:14]\[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[CH3:1][N:2]([C:10]1([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1(/C=C\c2cccnc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1(CCc2cccnc2)CC1

Procedure:
5.1 g of the product obtained in Step 1 dissolved in 120 ml of methanol are hydrogenated in the presence of 1 g of 10% palladium-on-carbon (20° C., 1 bar, 3 hours). The catalyst is filtered off and rinsed with methanol; concentrating to dryness and drying at 45° C. and 0.5 torr allows the desired product to be obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][N:5]([S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(NCC(OC)OC)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(N(CC(OC)OC)S(C)(=O)=O)ccc1F
Yield: 97.6 %

Procedure:
N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline (1.46 g, 6.37 mmol) in dichloromethane (20 ml) was treated with pyridine (0.5 g 6.37 mmol) and methanesulphonyl chloride (766 mg, 6.69 mmol) and the mixture stirred until the reaction was complete by tlc. Aqueous work up and removal of solvent in vacuo gave N-(2,2-dimethoxyethyl)-N-methanesulphonyl-4-fluoro-3-methoxyaniline 1.91 g
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([OH:25])=O)=[C:10]([CH2:12][C:13]3[C:21]4[C:16](=[C:17]([CH3:22])[CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].Cl.[OH:32][C@@H:33]1[CH2:37][O:36][NH:35][CH2:34]1>>[OH:32][CH:33]1[CH2:37][O:36][N:35]([C:23]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([CH3:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:25])[CH2:34]1
Reactant: O[C@H]1CNOC1
Reactant: Cc1cccc2c(Cc3sc4c(c3C(=O)O)c(=O)n(C)c(=O)n4CC(C)C)c[nH]c12
Agent: Cl
Product: Cc1cccc2c(Cc3sc4c(c3C(=O)N3CC(O)CO3)c(=O)n(C)c(=O)n4CC(C)C)c[nH]c12

Procedure:
Prepared using the procedure described in example 1 part g) from the product of step b) and (S)-4-hydroxyisoxazolidine hydrochloride [Example 1 part b] to give the title compound after purification by flash silica chromatography eluting with 0-3% methanol in ethyl acetate and recrystallisation from ethyl acetate:isohexane (9:1). MS (APCI) 497.1 [M+H] δ 1HDMSO 0.81-0.84 (6H,m), 2-2.1 (1H, m), 2.44 (3H, s), 3.2 (3H, s), 3.5-3.9 (6H, 3m), 4.1-4.2 (2H, m), 4.7-4.8 (1H,2m), 5.5 (1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H, m), 10.95 (1H, bs)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]4)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]2[C:30]([O:32][C:33](=O)[C:23]=2[CH:22]=1)=[O:31]>>[O:9]1[C:10]2[CH:20]=[C:19]3[C:14](=[CH:13][C:11]=2[N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([N:1]2[C:30](=[O:31])[C:24]4[C:23](=[CH:22][CH:21]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=4)[C:33]2=[O:32])[CH:7]=[CH:6][CH:5]=1)[CH:15]=[CH:16][CH:17]=[CH:18]3
Reactant: Nc1cccc(-c2nc3cc4ccccc4cc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cc5ccccc5cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)naphth[2,3-d]oxazole (36 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 30 mg (44%). 1H NMR (DMSO) δ 8.45(m, 2H), 8.38(d, 3H), 8.30(s, 1H), 8.12(m, 3H), 7.82(m, 2H), 7.55(m, 2H). MS 433 m/z (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:15])[CH3:14]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
17.0 g of 3-hydroxy-4-methoxy-benzoic acid and 51.6 g of acetic anhydride were combined and stirred at 140° C. for 3 h. Then 50 ml of water were added at 100° C., the mixture was heated under reflux for 30 min, another 200 ml of water were added and the mixture heated under reflux for 30 min. The mixture was cooled to 0° C., and the product was filtered off, washed with water and dried in vacuo to yield 18.8 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[Cl:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]3)[CH:22]=2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 99 %

Procedure:
Following general procedure D, tert-butyl 4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (54 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (60 mg, 99%) as a yellow-brown solid. ESI MS m/z 606 [C32H33ClFN5O4+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[Na].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 170) (15.2 g, 38.50 mmol) in ethanol (120 ml) was treated with portions of sodium borohydrideb (1.46 g, 38.50 mmol) and the resulting mixture was was stirred at room temperature under a nitrogen atmosphere for 5 hours. Aqueous citric acid (5%w/v, solution) was added slowly and the mixture was stirred at room temperature for a further 30 minutes. The organic solvent was removed under reduced pressure. The aqueous layer was diluted with water and extracted with ethyl acetate giving an emulsion. Anhydrous sodium chloride was added to break up the emulsion. The combined organic layers were washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (13.4 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[NH:23][CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1.N[C@H:27](C(O)=O)CCSC>CN(C=O)C.O>[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[N:23]([CH3:27])[CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(NC(=O)c3c(N)nn4cc(F)cnc34)cncc21
Yield: 19 %

Procedure:
NaH (3.958 mg, 0.09894 mmol) was added to a suspension of 2-amino-6-fluoro-N-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28 mg, 0.08995 mmol) (synthesized according to a procedure similar to Example 1 or Example 3a) and Met (11.49 mg, 5.039 μL, 0.08096 mmol) in DMF (3 mL) under N2. The suspension was stirred at RT for 5 h before water (2 drops) was added. The crude mixture was purified by fractionlynx HPLC. Clean fractions were liophilized to yield 2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5 mg, 16%). MS (ES+) 326.1.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1

Procedure:
7-Fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Example 1 but starting from 5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 16 g of 1-methylpiperazine in 50 cm3 of pyridine. After concentrating the reaction mixture
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OC(=O)c3ccccc3N)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
500 mg (1.35 mmol) of the compound of Example 6, 260 mg (1.59 mmol) of isatoic anhydride and 170 mg (1.39 mmol) of 4-dimethylaminopyridine were dissolved in 5 ml of dimethylformamide and the solution was stirred at 80° C. for 5 h. The solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. A precipitate thus formed was recrystallized from ethanol to obtain 500 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]1(=[O:47])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:41])/[CH:37]=[C:38](\[NH2:40])/[CH3:39])[C:22](=[O:42])[C:21]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:20]12>CO>[CH3:7][C:5]1[NH:40][C:38]([CH3:39])=[C:37]([C:36]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:19](=[O:47])[C:20]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:21]3[C:22]2=[O:42])=[O:41])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 97.8 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 9.33 g (37.5 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid methyl ester and 15.00 g (37.5 mmol) of 3-amino-crotonic acid-(11-phthalimido-undecyl)ester. 23.18 g (98%) of yellow crystals, melting point 130°-132° C., obtained from methanol.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:36])[C@@H:20]([CH2:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc3ccccc23)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Add formaldehyde (56 μL, 0.70 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (290 mg, 0.64 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (204 mg, 0.96 mmol) and stir 30 min at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2%) as the eluent to give 290 mg (97%) of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). HR-MS calculated for C29H31N4S: 467.2269. Found 467.2278. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[O:15])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].[H-].[Na+].C(O)(=O)C>O>[CH:1]1([C:4]2[C:13]([CH:14]([OH:15])[CH2:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 0.20 g (0.68 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL of acetonitrile and 0.042 g (1.06 mmol) of sodium hydride (purity: 60w). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture was added 0.08 mL (1.40 mmol) of acetic acid, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, to the mixture was added 10 mL of chilled water, and the mixture was extracted with 20 mL of ethyl acetate which were previously chilled in an ice bath. The organic portion was washed successively with 5 mL of saturated aqueous sodium hydrogen carbonate solution and 5 mL of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The organic portion was then filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography [column Wakogel C-200, available from Wako Junyaku Co., Ltd., eluent: ethyl acetate/hexane (7/93→15/85, vol. ratio)] to give 0.17 g (yield 75%) of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3-hydroxypropionitrile as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OCC)(=[O:12])C>>[Cl:9][C:3]1[C:2]([N:1]=[C:10]=[O:12])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: CCOC(C)=O
Product: Cc1ccnc(Cl)c1N=C=O

Procedure:
3-Amino-2-chloro-4-methylpyridine (4.3 g) was added to a solution of trichloro-methyl chloformate (6.0 g) in ethyl acetate (100 ml) at 0° to 5° C. with stirring and the mixture was refluxed under heating for 6 hours. After removal of the solvent under reduced pressure, 2-chloro-4-methyl-3-pyridylisocyanate (4.9 g) was obtained. A mixture of 2-chloro-4-methyl-3-pyridylisocyanate (4.9 i) and trimethylsilyl azide (11 g) was refluxed under heating for 30 hours. After removal of excess trimethylsilyl azide under reduced pressure, methanol was added to the resulting residue. Thereafter, the methanol was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (eluent chloroform:ethanol=15:1) to obtain the desired 1-(2-chloro-4-methyl-3-pyridyl)-5(4H)-tetrazolinone (3.0 g). m.p. 160°-162° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@@H:6]1[OH:12])=[O:4].[OH-].[Na+]>CO>[OH:12][C@H:6]1[CH2:7][C@H:8]([CH3:11])[CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of (1R,2S,4R)-2-Hydroxy-4-methyl-cyclohexanecarboxylic acid methyl ester (450 mg, 2.42 mmol) in methanol (12 ml) was added a 2.5 M solution of sodium hydroxide (9.7 ml, 24.2 mmol). The reaction mixture was stirred for 4 h at 50° C. Then, the solvents were removed and the residue was partitioned between 20 ml of H2O acidified to pH 4 and 20 ml of EtOAc. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2×20 ml). The combined ethyl acetate layers were dried (Na2SO4) and concentrated to obtain 313 mg (82%) of (1R,2S,4R)-2-Hydroxy-4-methyl-cyclohexanecarboxylic acid. NMR 1H (CDCl3, 400 MHz): 4.34 ppm (s, 1H); 2.43-2.39 ppm (m, 1H); 1.96-1.76 ppm (m, 5H); 1.14-1.08 ppm (m, 1H); 1.02-0.93 ppm (m, 1H); 0.90 ppm (d, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:22][C:23]1[N:24]=[N:25][C:26](Br)=[CH:27][CH:28]=1>CN(C)C=O>[Br:22][C:23]1[N:24]=[N:25][C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=3)[CH2:11][CH2:12]2)=[CH:27][CH:28]=1
Reactant: Brc1ccc(Br)nn1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(c3ccc(Br)nn3)CC2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 5 parts of 1-(3-methylphenyl)piperazine dihydrochloride, 10.6 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred for 1 hour at 65° C. Then there were added 7.2 parts of 3,6-dibromopyridazine and the whole was stirred overnight at about 65° C. The reaction mixture was poured into ice water. The product was filtered off and dissolved in dichloromethane. The solution was washed twice with water, dried, filtered and evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 4.1 parts (61.5%) of 3-bromo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 145.7° C. (compound 136).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][CH2:53][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN1CCCNCC1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.402 mmole), 1-methyl-1,4-diazepane (0.23 g, 0.25 mL, 2.00 mmoles) in DMSO was stirred at 85° C. for 2.5 h. The suspension was poured onto ice-water, filtered and re-dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH—with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which taken on directly to the next step. HPLC retention time 5.96 mins.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[S:8])SC.[N-:9]=[N+:10]=[N-:11].[Na+].O>O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]1[C:5]([SH:8])=[N:11][N:10]=[N:9]1
Reactant: CSC(=S)NCCO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCCn1nnnc1S
Yield: 4.8 %

Procedure:
A mixture of methyl N-(2-hydroxyethyl)dithiocarbamate (3.7 g.), sodium azide (2.4 g.), water (20 ml.) and dioxane (20 ml.) was heated under reflux for four hours. After the dioxane was removed from the mixture under reduced pressure, the aqueous solution was washed with ether. The solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give oily product (0.47 g.). The oily product was purified by column chromatography on silica gel to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (0.17 g.). m.p. 135° to 137° C.