Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.C1COCC1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[OH:22][CH2:21][CH:20]([NH:19][C:14](=[O:15])[O:16][CH2:17][CH3:18])[CH2:23][OH:24]
Reactant: CCOC(=O)Cl
Reactant: NC(CO)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NC(CO)CO
Reaction time: 4 h
Yield: 54.5 %

Procedure:
In a 1 liter round bottom flask with magnetic stir bar, serinol (10.0 g) and Na2CO3 (25.0 g) were dissolved in the mixture of DI water (250 mL) and THF (150 mL). The reaction mixture was allowed to cool in ice. Ethyl chloroformate (10.5 mL) was added drop-wise and the reaction was allowed to proceed in ice for 4 hours, followed by about 16 hours at room temperature. Another 100 mL of DI water was added to the reaction mixture and the product was extracted into ethyl acetate (20×100 mL). The crude product (11.6 g) was further purified by flash column chromatography, using silica as the packing material and CH3OH:CHCl3 (1:9) mixture as the eluent. The final product was a transparent viscous oil that was crystallized in the presence of trace ethyl acetate (1 to 2 mL) along with vigorous scratching using a spatula. The crystallized product was washed with cold ethyl acetate:hexanes (1:1) mixture (1×100 mL), and dried under vacuum to result in white crystalline solid (8.9 g, 54.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CC(N(C)C)=O>[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH:33][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccc4[nH]ccc4c3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc(-c3ccc4[nH]ccc4c3)c3ccccc3n2)cc1
Temperature: 50 °C
Yield: 4.4 %

Procedure:
To a round bottomed flask containing 4-(4-(1H-indol-5-yl)quinazolin-2-ylamino)-benzoic acid (428 mg, 1.13 mmol) was added 2,6-dimethylaniline (137 mg, 1.13 mmol), HATU (428 mg, 1.13), Hunig's base (400 μL, 2.3 mmol), and dimethylacetamide (4 mL). The stirred mixture was heated to at 50° C. for 14 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 5% aqueous lithium chloride and saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude material was purified by preparative reverse phase HPLC to afford N-(2,6-dimethylphenyl)-4-{[4-(1H-indol-5-yl)quinazolin-2-yl]amino}benzamide as a yellow solid (24 mg, 5%). 1H NMR (400 MHz, DMSO-d6): δ 11.45 (s, 1H), 10.23 (s, 1H), 9.60 (s, 1H), 8.19 (d, 2H), 8.02 (m, 4H), 7.83 (m, 2H), 7.62 (m, 2H), 7.51 (m, 1H), 7.41 (m, 1H), 7.13 (s, 3H), 6.63 (m, 1H), 2.20 (s, 6H). MS (EI) C31H25N5O: 484.2 (MH+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]1([C:12]([OH:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[SH:2][O:5][C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13].[Cl:1][S:2]([O:13][C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Product: O=C(OS(=O)(=O)Cl)c1ccccc1
Product: O=C(OS)c1ccccc1
Temperature: 0 °C

Procedure:
In one step, a mercaptophenylcarboxylic acid is prepared, preferably from the following general procedure. Chlorosulfonic acid is added, preferably dropwise, to a reaction vessel containing a phenylcarboxylic acid. The reaction vessel is preferably equipped with a mechanical stirrer or other agitation means. About 2 to about 20 mols of chlorosulfonic acid are utilized per mol of phenylcarboxylic acid while maintaining the temperature of the reaction mixture at about 0° C. plus or minus about 10° C. The mixture is allowed to warm to room temperature over an extended period of time, such as about 12 hours, and then added, preferably dropwise, to an excess of crushed ice in order to precipitate the mercaptophenylcarboxylic acid. The mercaptophenylcarboxylic acid is collected by suction filtration and dissolved in a solvent such as ethyl acetate. The organic layer is separated from the aqueous layer and washed with a quantity of water, subsequently dried over a suitable drying agent such as anhydrous sodium sulfate, and then evaporated to yield chlorosulfonylphenylcarboxylic acid. Often, an isomeric mixture is formed. If desired, the individual isomers can be isolated from this mixture by utilizing conventional separation techniques such as recrystallization or column chromatography.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8](=[O:17])[CH:9]([O:11][C:12]([CH3:16])([CH3:15])[C:13]#[CH:14])[CH3:10]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[CH3:6][O:7][C:8](=[O:17])[CH:9]([O:11][C:12]([CH3:16])([CH3:15])[C:13](=[O:2])[CH3:14])[CH3:10]
Reactant: O=S(=O)(O)O
Reactant: C#CC(C)(C)OC(C)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Product: COC(=O)C(C)OC(C)(C)C(C)=O
Temperature: 60 °C
Yield: 141.7 %

Procedure:
A mixture of mercury (II) acetate (7.76 g, 0.024 mol), sulfuric acid (9 ml, 0.09 mol) and water (450 ml) is heated at 60° C. 2-(1,1-dimethylprop-2-ynyloxy)propionic acid methyl ester (90 g, 0.529 mol) is added carefully at 60° C. The reaction mixture is maintained at 60° C. for 8 hours and cooled to ambient temperature. The aqueous phase is extracted with diethyl ether (3×250 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-(1,1-dimethyl-2-oxopropoxy)propionic acid methyl ester (24 g) as a colorless oil.
Reaction SMILES: C[C:2]([N:5](C([O-])=O)[N:6]=[C:7](C1C=CC([Cl:24])=CC=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[N:14][N:13]([CH3:16])[C:12]=2[CH:17]=1)([CH3:4])[CH3:3].[ClH:28].O.O1C[CH2:33][CH2:32][CH2:31]1>>[ClH:24].[Cl:28][C:32]1[CH:33]=[CH:3][C:2]([NH:5][NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13]([CH3:16])[C:12]=3[CH:17]=2)=[CH:4][CH:31]=1
Reactant: Cn1nnc2ccc(C(=NN(C(=O)[O-])C(C)(C)C)c3ccc(Cl)cc3)cc21
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 10 g of intermediate 1-b in 60 ml of tetrahydrofuran under a nitrogen atmosphere were added dropwise over 15 minutes 26 ml of a borane tetrahydrofuran complex in tetrahydrofuran (1M). After stirring for 15 minutes at ±22° C. there were added 13 ml of hydrochloric acid (6N). The whole was heated to reflux and refluxed for 1.5 hours. The mixture was cooled to room temperature and 50 ml of water were added. After stirring for 1 hour, the reaction mixture was filtered. The filtrate was mixed with 75 ml of methylbenzene. The layers were separated and the aqueous layer was basified (pH 7.5-8) with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol by adding 3 ml of a mixture of hydrochloric acid in 2-propanol (4.8N). After stirring for 2 hours the product was filtered off, washed with 2-propanol and dried in vacuo at 50° C., yielding 2.1 g of (±)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole monohydrochloride (interm. 2-e).
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](Cl)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:27][C:28]1[CH:29]=[C:30]([C:38]([O:40][CH3:41])=[O:39])[CH:31]=[C:32]([CH:37]=1)[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C.O>O1CCCC1>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([NH:27][C:28]1[CH:37]=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[C:30]([CH:29]=1)[C:38]([O:40][CH3:41])=[O:39])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-decyltetradecanoyl chloride from Step 1 in dry tetrahydrofuran (80 mL) was added dropwise slowly to a suspension of dimethyl 5-aminoisophthalate (Sigma-Aldrich, 4.40 g, 21.0 mmol), triethyl amine (4.4 mL, 31.5 mmol), and dry tetrahydrofuran (100 mL) under an inert atmosphere at 0° C. The reaction was allowed to warm slowly to room temperature and was stirred overnight. Deionized water (10 mL) was added and the tetrahydrofuran was removed by rotary evaporation. The crude residue was then dissolved in 250 mL of ethyl acetate and washed with 3 successive 100 mL portions of deionized water. The ethyl acetate was then removed from the organic phase by rotary evaporation and the product was dried in vacuo to give crude dimethyl 5-(2′-decyltetradecanamido)isophthalate (12.56 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:28]([CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CNCc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CN(Cc1ccccn1)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-methyl-1-(pyridin-2-yl)methanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methyl-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 491 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:20]([CH:23]=[O:24])=[CH:21][N:22]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2.[BH4-].[Na+]>CO.O>[OH:24][CH2:23][C:20]1[N:8]2[C:9]3[C:14]([N:15]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2=[N:22][CH:21]=1)=[CH:13][C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=3
Reactant: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(CO)cnc12
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of the 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline-1-carbaldehyde prepared as in example 36 (8 mg, 0.024 mmol) in anhydrous methanol (300 μL), cooled at 0° C. was added sodium borohydride (2 mg, 0.047 mmol). The mixture was allowed to warm to room temperature over 1 h under argon and then diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 9/1) to afford the title compound as a white solid (5 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5].[C:9](OC(=O)C)(=[O:11])[CH3:10].CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:7]([CH:3]([C:4](=[O:6])[CH3:5])[CH2:2][O:1][C:9](=[O:11])[CH3:10])[CH3:8]
Reactant: CCC(CO)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(COC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxymethyl-pentan-2-one (20.7 g) was dissolved in CHCl3 (150 mL) and cooled in an ice bath. Acetic anhydride (80 mL) was added, followed by DMAP (2.18 g), and the mixture was stirred overnight at room temperature. After cooling in an ice bath, MeOH (120 mL) was added dropwise, and the mixture was poured into a saturated aqueous NaHCO3 solution. After extraction with DCM twice, the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 28.0 g of a light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 3H), 1.46-1.75 (m, 2H), 2.03 (s, 3H), 2.20 (s, 3H), 2.77 (quint., J=6.5 Hz, 1H), 4.20 (d, J=7 Hz, 3H).
Reaction SMILES: C([C:3]1([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#N.Cl.[C:22](=[O:25])([O-])[O-:23].[Cs+].[Cs+].[Si](Cl)(C)(C)[CH3:29]>CO>[CH3:18][Si:17]([CH3:19])([CH3:20])[O:16][C:3]1([C:22]([O:23][CH3:29])=[O:25])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(O[Si](C)(C)C)C1
Reactant: C[Si](C)(C)Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CO
Product: COC(=O)C1(O[Si](C)(C)C)CCCNC1
Reaction time: 1 h

Procedure:
tert-Butyl 3-cyano-3-(trimethylsilyloxy)piperidine-1-carboxylate, Preparation 34A (170 mg, 0.570 mmol) was treated with 6N HCl in MeOH (10 mL) at 80° C. for 12 hours. Solvents were removed in vacuo and the resulting material was dissolved in MeOH (10 mL). HCl (g) was bubbled through the mixture for 15 minutes. The solids were concentrated in vacuo. The residue was dissolved in DCM (10.00 mL) and cesium carbonate (928 mg, 2.85 mmol) was added. Next, TMS—Cl (0.146 mL, 1.139 mmol) was added and the mixture was stirred for 1 hour. The mixture was filtered and the solids were concentrated in vacuo and taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>ClC(Cl)C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 8 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
A solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (26.7 g, 0.112 mol) and benzene (12.0 mL, 0.134 mol) in 1,1,2,2-tetrachloroethane is cooled to 0° C. to 5° C., treated with aluminum chloride (18.1 g, 0.136 mol), stirred for 15 minutes at about 8° C., heated to and stirred at 50° C. for one hour, cooled to room temperature, and diluted sequentially with an ice-water mixture and concentrated hydrochloric acid. The organic phase is separated, washed-sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride gives the title product as an orange solid (30.8 g) which is identified by NMR spectral analyses.
Reaction SMILES: O([C:8]([NH:10][N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1)=[O:9])C1C=CC=CC=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1>CN(C)C1C=CN=CC=1.ClCCCl>[N:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8]([NH:10][N:11]2[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]2)=[O:9])=[N:19][CH:20]=1
Reactant: Nc1ccncn1
Reactant: O=C(NN1CC=CCC1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(Nc1ccncn1)NN1CC=CCC1
Yield: 64.4 %

Procedure:
A mixture of N-(phenoxycarbonylamino)-1,2,3,6-tetrahydropyridine (2.61 g), 4-aminopyrimidine (0.95 g) and 4-dimethylaminopyridine (1.83 g) in 1,2-dichloroethane (80 ml) was refluxed for 2.5 hours. The reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate (50 ml) and washed with water (50 ml), and then extracted with 5% hydrochloric acid (30 ml×2). The extract was neutralized with sodium bicarbonate and further extracted with chloroform (30 ml×2). The chloroform layer was washed with water (50 ml), dried over magnesium sulfate and evaporated to give N-[(4-pyrimidinylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (1.41 g), which was recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2cnc(NCCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 65 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-morpholinopropan-1-amine. The crude product was purified by flash column chromatography (5% methanol in methylene chloride) to give a yellow solid (0.065 g, 65%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 2.4 (d, J=13.1 Hz, 6 H) 3.3 (dd, J=12.9, 6.8 Hz, 2 H) 3.6 (m, 4 H) 6.9 (m, 2 H) 7.3 (m, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (dd, J=6.8, 2.5 Hz, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.7 (s, 1 H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:25]4=[C:26]([C:28](=[O:38])[C:29]([CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][N:24]4[C:23]4[CH:22]=[C:21]([Br:39])[CH:20]=[CH:19][C:18]=4[S:17]3)[CH:27]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:39][C:21]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:25]4=[C:26]([C:28](=[O:38])[C:29]([CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][N:24]4[C:23]=2[CH:22]=1)[CH:27]=[C:14]([O:13][CH2:12][C:8]1[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=1)[CH:15]=3
Reactant: CC(=O)OCc1cncc(COc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4cncc(CO)c4)cc13)Sc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
The compound (220 mg) obtained in Example 41 was suspended in methanol(10 mL) and to the suspension was added dropwise a solution of sodium hydroxide (90 mg) in water (1 mL). The mixture was stirred at room temperature overnight. After the end of reaction, the precipitate crystals were collected by filtration and washed with methanol and ether in turns to obtain the title compound (180 mg; 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[NH:9][C:8](=[O:31])[CH2:7][C:6]=2[CH:32]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[NH:9][C:8](=[O:31])[CH2:7][C:6]=2[CH:32]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)Cc1cc(N)ccc1-2
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccc2c(c1)CC(=O)Nc1c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn1-2

Procedure:
Compound 75 was prepared from 8-amino-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide and acryloyl chloride according to the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 7.85-7.79 (m, 3H), 7.75-7.71 (m, 2H), 7.43-7.37 (m, 2H), 7.20-7.14 (m, 1H), 7.12-7.06 (m, 4H), 6.50-6.35 (m, 2H), 5.81 (dd, J=2.6, 9.0 Hz, 1H), 3.75 (s, 2H). MS (ESI) m/e [M+1]+ 480.1.
Reaction SMILES: Cl.[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(Cl)([Cl:33])=O>CC(OC)(C)C.O.C1(C)C=CC=CC=1>[ClH:33].[C:2]1([C@H:12]([NH:14][CH2:15]/[CH:16]=[CH:17]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 60 °C

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (50.0 g, 121.990 mmol) is suspended in MTBE (200 ml) and water (80 ml) at room temperature. Sodium hydroxide (30% w/w aqueous solution) is added drop-wise (17.1 g, 128.250 mmol) in order to control the exothermic reaction and the mixture is stirred until the starting solid dissolves completely. The organic layer is then separated and washed repeatedly with water up to neutral pH. Thus MTBE is flushed with toluene and thionyl chloride (16.7 g, 140.372 mmol) is added slowly to the resulting toluenic solution, while maintaining 10°-20° C. The reaction mixture is heated up to 60° C. and maintained for 4 hrs, or until positive IPC (via HPLC). At reaction completion MTBE is charged (170 ml) and the mixture is heated up to 80°-85° C. and trace water is removed azeotropically. The mixture is cooled down to 60° C., MTBE is restored, then cooled down to 10° C. and aged two hours. 46.1 g of a 96.2:3.8 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydrochloride (XI) is obtained as a white powder after filtration, washing with a 1:1 vol/vol toluene/MTBE mixture (3×40 ml) end exsiccation at 55° C. under vacuum.
Reaction SMILES: C([Si:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1)=CCCC.[Br-].[O:21]([C:29]1[CH:54]=[CH:53][C:32]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:31][CH:30]=1)[Si](C(C)(C)C)(C)C.Br[CH2:56][C:57]([F:62])([F:61])[CH:58]([F:60])[F:59]>>[F:61][C:57]([F:62])([CH:58]([F:60])[F:59])[CH2:56][O:21][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][CH2:12][C@H:9]2[CH2:8][CH2:7][Si@H:6]([CH2:14][CH2:19][CH2:18][CH:17]=[CH2:16])[CH2:11][CH2:10]2)=[CH:53][CH:54]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)C(F)(F)CBr
Reactant: CCCC=C[Si]1(c2ccccc2)CCC(C=O)CC1
Agent: [Br-]
Product: C=CCCC[Si@H]1CC[C@H](CCc2ccc(OCC(F)(F)C(F)F)cc2)CC1

Procedure:
The general procedure of Example 56 was repeated using 4-n-pentenyl-4-phenyl-4-silacyclohexane carbaldehyde, 4-(t-butyldimethylsiloxy)benzyltriphenylphosphonium bromide, and 1-bromo-2,2,3,3-tetrafluoropropane, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:10]([CH3:9])[CH:11]2[CH2:27][CH2:26][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol) and tert-butyl 8-(methylamino)-2-azaspiro[4.5]decane-2-carboxylate (1.29 g, 4.8 mmol) in EtOH (10 mL) was added Et3N (0.92 g, 9.1 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the product as a pale yellow solid (580 mg, 38.1%).