Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[S:13][CH:14]=[CH:15][C:5]=3[C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1.[H-].[Na+].Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>C1COCC1>[CH:38]([O:37][C:35]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[S:13][CH:14]=[CH:15][C:5]=3[C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: CC(C)OC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of tert-butyl 1-(4-(8-hydroxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (44 mg, 0.10 mmol) in THF (2 mL) at 0° C. was added NaH (60%, 6 mg, 0.15 mmol) and the reaction was stirred at that temperature for 1 h. Isopropyl chloroformate (21 μL, 0.15 mmol) was added and the resulting mixture was stirred at rt for 3 h. Water was added and the mixture was extracted with dichloromethane (2×15 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (heptane/ethyl acetate) to afford the desired product (26 mg, 50%) as a solid: ESI MS m/z 523 [C28H30N2O6S+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8].[CH3:9][S-:10].[Na+]>CO>[CH3:8][C:3]1[N:4]=[C:5]([NH2:7])[S:6][C:2]=1[S:10][CH3:9]
Reactant: Cc1nc(N)sc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1sc(N)nc1C
Reaction time: 8 h

Procedure:
5-Bromo-4-methyl-thiazol-2-ylamine (1.35 g, 7 mmol,) was dissolved in methanol abs. (13.5mL) and sodium methanethiolate (0.6 g, 7.7 mmol) 1.1 equiv.) was added portionwise at rt. After stirring overnight, the dark colored mixture was concentrated under reduced pressure and purified over a 50 g silica cartridge (NH2-modified) with ethyl acetate as eluent. The desired fractions were evaporated to give the title compound as a light yellow solid: 180 mg, MS (ISP): m/e 161.1 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][S:20][C:16]=4[C:15](=[O:21])[N:14]([CH3:22])[CH2:13][C:12]=23)[O:6][CH:7]=1.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>O1CCCC1>[CH2:23]([N:26]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][S:20][C:16]=4[C:15](=[O:21])[N:14]([CH3:22])[CH2:13][C:12]=23)[O:6][CH:7]=1)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2ccsc2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)n1
Yield: 37.7 %

Procedure:
0.167 g (0.000498 mol) of 3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one was dissolved in 20 ml of tetrahydrofuran, treated with 1.4 ml (0.0102 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 1:1 as the eluent and recrystallized from diisopropyl ether. There was obtained 0.075 g (38%) of 3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as white crystals; m.p. 110-111°.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[Si:20]([O:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CS[C@@H](CO)C(=O)N1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CS[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above crude compound (11, 9.0 g, 0.057 mol) in DCM (150 mL) was added imidazole (7.70 g, 0.113 mol) followed by tert-butyl(chloro)diphenylsilane (17.2 g, 0.0630 mol) under N2 atmosphere. After the addition, the resulting solution was stirred at ambient temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with DCM (3×200 mL). The combined organic fractions were concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (PE: EtOAc=10:1 to 2:1) to give (2S,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-methylthiomorpholin-3-one (12) that gave a proton NMR spectra consistent with theory.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][O:15][CH3:16])=[N:9]1)C1C=CC=CC=1>CO>[CH3:16][O:15][CH2:14][C:10]1[C:11]([CH3:13])=[CH:12][NH:8][N:9]=1
Reactant: COCc1nn(Cc2ccccc2)cc1C
Solvent: CO
Product: COCc1n[nH]cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 122.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1-benzyl-3-(methoxymethyl)-4-methyl-1H-pyrazole (compound 268.3, 700 mg, 3.24 mmol) in methanol (10 mL). The system was purged with nitrogen, then Pd(OH)2/C (70 mg, 20 wt %) and aqueous HCl (2 M, 0.3 mL) were carefully added. The system was then charged with hydrogen (1 atm) and the resulting mixture was stirred for 2 days at room temperature. The system was purged with nitrogen, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to 7 with aqueous sodium bicarbonate (sat.) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil (500 mg, crude).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:11])=[CH:6][CH:5]=2.[H-].[Na+].Cl[C:15]1[N:16]=[C:17]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:18]2[S:23][C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[CH:21][C:19]=2[N:20]=1>CN(C=O)C.O.[Cl-].[Na+]>[F:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([C:15]1[N:16]=[C:17]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:18]3[S:23][C:22]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[CH:21][C:19]=3[N:20]=1)[C:2]([CH3:1])=[CH:10]2
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc(F)ccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 10.4 %

Procedure:
A solution of 2-methyl-5-fluoroindole (0.164 g) in DMF (6 mL) was cooled to 0° C. then sodium hydride (0.066 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 3 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The resulting residual oil was separated from the aqueous layer, and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 119 (0.053 g, 10%) as a yellow solid. MS m/e 509 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, 2H) 2.08 (t, 3H) 2.18 (s, 6H) 2.64 (s, 3H) 2.95 (d, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.42 (s, 1H) 6.98-7.20 (m, 1H) 7.37 (m, 1H) 7.43 (s, 1H) 8.03 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1>CC(C)=O>[CH3:9][C:8]1([CH3:13])[O:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1]1
Reactant: OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 6265.8 %

Procedure:
In a pear-shaped flask equipped with a calcium tube, a condenser, and a Dean-Stark trap, 100 g of glycerine, 300 ml of acetone, 3 g of p-toluenesulfonic acid monohydrate, and 300 ml of petroleum ether were placed, and heated to reflux in an oil bath set at 50° C. After 12 hours, when about 23 ml of water was collected and no further formation of water was confirmed, the reaction mixture was cooled to room temperature. 3 g of sodium acetate was added, and the mixture was stirred for 30 minutes. Petroleum ether and acetone were distilled off in an evaporator. The resulting crude product was purified by vacuum distillation to give 130.6 g of 2,3-O-isopropylideneglycerol in the form of colorless, transparent liquid at 91% yield. 1H-NMR spectral data are shown below:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3OC(F)(F)F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2-(trifluoromethoxy)benzoyl chloride (37 μL, 0.229 mmol) and mixing for 24 h, 49.8 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27].ClCCl>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:27]#[C:26][CH2:25][OH:28])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.012 g), and propargyl alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Dichloromethane followed by hexanes is added to the reaction mixture. The resulting solid is filtered, washed thoroughly with hexanes, and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 0.5% MeOH:CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.13 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 4-propylphenylboric acid (0.49 g), cupric acetate (0.27 g), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) as a light yellow, oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.51 g of 3-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 7.97 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 3.6 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(3-dimethylaminobenzoyl)-piperazine having a melting point of 110°-112° is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:17](O)=[O:18])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH2:17][OH:18])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1
Reactant: COC(=O)CCCCCCc1nc(C)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)CCCCCCc1nc(C)sc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4.15 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid (X, R1 = CH3) in 50 ml of anhydrous benzene 4.2 ml of oxalyl chloride were added dropwise, and the reaction mixture was allowed to stand overnight at room temperature, then benzene and excess oxalyl chloride were evaporated in vacuo. The obtained residue containing 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid chloride (XI, R1 = CH3) was dissolved in 20 ml of anhydrous dioxane, and a suspension of 1.1 g of sodium borohydride in 20 ml of anhydrous dioxane was added dropwise to the solution under continuous stirring. Stirring of the reaction mixture was continued for 30 minutes at room temperature and for further 60 minutes at 80° C. When the reaction mixture was cooled to room temperature, 25 ml of water were dropwise added under ice-cooling to the reaction mxiture, and stirring was continued for 2 hours at room temperature. Subsequently, the aqueous reaction mixture was extracted with 3 × 50 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo, yielding 2.95 of crude product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccccc2)C[C@H](C)N3C(C)=O)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 54) (104 mg, 0.206 mmol) in dichloromethane (DCM) (3 mL) at room temperature under nitrogen was treated with trifluoroacetic acid (TFA) (0.5 mL, 6.49 mmol) and the resulting mixture was stirred at this temperature for 1 h then concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine trifluoroacetate (99 mg, 0.191 mmol, 93% yield) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[CH:29](I)([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(5-hydroxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.56 mmol) in acetone (5 mL) cooled to 0° C. was added isopropyliodide (0.33 g, 1.96 mmol) and K2CO3 (0.43 g, 3.12 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was evaporated to dryness and water (10 mL) was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1:19 acetone:hexane) to give the title compound (0.5 g, 75%). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=3.3 Hz, 1H), 7.28 (m, 2H), 6.96 (d, J=7.5 Hz, 1H), 6.91 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 6.32 (s, 1H), 4.45 (m, 1H), 3.49 (m, 2H), 3.38 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 1.47 (s, 9H), 1.33 (d, J=6 Hz, 6H); m/z (425.2, M+ H+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:37]3[CH:42]=[C:41]([C:43](=[O:48])[NH:44][CH:45]4[CH2:47][CH2:46]4)[CH:40]=[C:39]([F:49])[C:38]=3[CH3:50])[CH:18]=2)[C:13]1=[O:51])(C(C)(C)C)(C)C.C(O)C>Cl.O1CCOCC1>[CH:45]1([NH:44][C:43](=[O:48])[C:41]2[CH:42]=[C:37]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:51])[N:12]([CH2:11][C:10]([CH3:53])([CH3:52])[CH2:9][OH:8])[CH:21]=[C:20]4[CH:22]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH3:23])[C:38]([CH3:50])=[C:39]([F:49])[CH:40]=2)[CH2:47][CH2:46]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C(C)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C(C)N3CCNCC3)c2c1
Yield: 101.6 %

Procedure:
A solution of tert-butyl 4-(1-{2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}ethyl)piperazine-1-carboxylate (Example 38c, 80 mg) in 4 M HCl in dioxane (1 mL) and ethanol (3 mL) was stirred overnight at room temperature before the volatiles were removed in vacuo. The crude material was dissolved in methanol (2 mL) and loaded onto a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1 N methanolic ammonia (50 mL) and evaporated in vacuo to afford the title product (58 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1C(F)(F)F
Product: O=C(Cl)c1ccncc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 0.72 g of 3-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to give 3-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 3-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.66 g of 2-amino-4-trifluoromethylphenol, 0.76 g of triethylamine, 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour and stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.62 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:12]=[N:13][C:14]([C:28]#[N:29])=[C:15]([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:19][CH2:18]2)[N:16]=1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:12]=[N:13][C:14]([C:28]#[N:29])=[C:15]([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:19][CH2:18]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nnc(NCCN)nc1N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 60 mg (0.15 mmol) of {2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester as prepared in example 8 in 2 ml of dichloromethane were added 0.2 ml of trifluoroacetic acid. The reaction mixture was stirred at room temperature for one hour and then evaporated under reduced pressure. The solid residue was dispersed in ether. The resulting solid was filtered and gave 30 mg (47% of theory) of 3-(2-amino-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile trifluoro-acetate as an off-white solid; MS: 310 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CC=CCO2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(N2CC=CCO2)c(Cl)c1

Procedure:
Prepared analogously to Example 2d from methyl 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate and sodium hydroxide in a solvent mixture of water and ethanol.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH2:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH:17][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][OH:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCO1
Reactant: NCC1c2ccccc2CCc2ccccc21
Product: O=C(CCCO)NCC1c2ccccc2CCc2ccccc21

Procedure:
10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-methylamine (8.5 g) and γ-butyrolactone (3.7 g) are heated at 150° C. (internal temperature) for 1 hour. After cooling, the solid residue is recrystallized from benzene to give N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-hydroxybutyramide, (III, Alk = CH2CH2CH2 and Y = OH), m.p. 103°-105° C.