Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:39])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:29]2[CH:34]=[CH:33][C:32]([O:35]COC)=[CH:31][CH:30]=2)=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1>CO>[ClH:1].[CH3:39][N:3]([CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[CH:9][CH:8]=1
Reactant: COCOc1ccc(C(=C(c2ccc(OCOC)cc2)C(F)(F)F)c2ccc(OCCN(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Product: CN(C)CCOc1ccc(C(=C(c2ccc(O)cc2)C(F)(F)F)c2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 74.4 %

Procedure:
10 ml of a 9% methanolic hydrochloric acid are added to a solution of 4.0 g (7.47 mmoles) of 1-[4-(2-dimethylaminoethoxy)-phenyl]-3,3,3-trifluoro-1,2-bis-(4-methoxymethoxyphenyl)-propene in 40 ml of methanol, and the mixture is boiled for one hour. The solution is evaporated to dryness, and the residue is crystallized from ethanol. 2.67 g (74.4%) of the desired compound are obtained; m.p.: 256°-262° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].Cl[C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=2[N:11]=1>CO>[OH:3][NH:2][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: NO
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: ONc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 20 °C
Yield: 56.3 %

Procedure:
21.81 g of hydroxylamine hydrochloride are added to 17.61 g of potassium hydroxide in solution in 350 ml of methanol at a temperature in the region of 20° C. and the reaction mixture is brought to reflux for 10 minutes. 13.24 g of 2-chloro-6-(trifluoromethoxy)benzothiazole are then added and the reaction is continued at reflux for 5 hours. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered off and the filtrate concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa). The crude product thus obtained is purified by flash chromatography on a silica column, using an ethyl acetate/cyclohexane (20/80 by volume) mixture as eluent. 7.35 g of 2-hydroxyamino-6-(trifluoromethoxy)benzothiazole are thus isolated in the form of an orangey-yellow powder melting with decomposition at 119° C. [(Analysis % calculated C: 38.40, H: 2.01, F: 22.78, N: 11.20, S: 12.82; % found C: 38.7, H: 1.9, F: 22.3, N: 11.1, S: 12.6); 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, at a temperature of 373 K, δ in ppm): 7.22 (mt, 2H, H 4 and H 5), 7.62 (broad s, 1H, H 7), 9.55 and from 9.50 to 11.00 (respectively broad s and unresolved peak, each 1H, NHOH)].
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[C:7]=1[Cl:17])C.[OH-].[K+].O>C(O)C>[Cl:17][C:7]1[C:8]2[C:13](=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2cc(Cl)ccc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of N-(1,6-dichloro-2-naphthyl)carbamic acid ethyl ester (750 mg, 2.64 mmol) and KOH (1.78 mg, 31.7 mmol) in ethanol (20 mL) is heated to reflux temperature under a N2 atmosphere for 12 hours. After cooling to room temperature, water (10 mL) is added. The resulting precipitation is removed by filtration to give 1,6-dichloro-2-aminonaphthalene as a solid.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3N(C)C(C)=NC=3)O)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[CH3:39][C:40]1[N:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:41]=1[CH:42]=[O:43]>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:42]([C:41]3[C:40]([CH3:39])=[N:47][C:46]([CH3:48])=[CH:45][CH:44]=3)[OH:43])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.6 mL, 4.0 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.711 g, 3.964 mmol, Intermediate 45: step d) in dry THF (20 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 2,6-dimethylnicotinaldehyde (0.8 mL, 6.3 mmol) in dry THF (6 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19][Cl:20])=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[CH:4][C:3]1[C:6]([Cl:11])=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:17](=[O:18])[CH2:19][Cl:20])[CH3:13]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Product: CCOC(=O)C(=Cc1c(Cl)ccc(Cl)c1Cl)C(=O)CCl

Procedure:
210 g of 2,3,6-trichlorobenzaldehyde were reacted with 4-chloroacetoacetic acid ethyl ester as described in Example 43. 213 g of a 3:1 isomer mixture were obtained as an oily crude product.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:3].P([N:33]=[N+:34]=[N-:35])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[N:33]([CH:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:3])=[N+:34]=[N-:35]
Reactant: COC(=O)c1ccc2cc(C(C)O)oc2c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(C(C)N=[N+]=[N-])oc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
To a solution of methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (1.10 g, 4.99 mmol) in toluene (20 mL) were added diphenyl azidophosphate (1.62 mL, 7.50 mmol) and DBU (1.50 mL, 9.98 mmol), and the mixture was stirred at room temperature for 2.5 hr. Ethyl acetate was added thereto, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 2:3) to give the title compound (1.22 g, yield 88%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5](=[CH:10][CH:11]=1)[CH2:6][C:7]([OH:9])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:19]2[C:7](=[O:9])[CH2:6][C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[C:12]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(=O)O
Product: O=C1Cc2ccc(Cl)cc2C(=O)N1c1cccc(Cl)c1

Procedure:
A mixture of 4-chlorohomophthalic acid (54.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) is heated by an oil bath until molten for two hours. When removed from the oil bath, the reaction mixture solidifies and is recrystallized twice from ethanol/ethyl acetate, giving 2-(m-Chlorophenyl)-7-chloroisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH3:41])[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[C:34]([O:40][CH3:41])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cc(OC)cc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)cc(C(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 858.5 %

Procedure:
To the product from Example 194 (800 mg, 0.00014 mole) in H2O (20 mL) and CH3CN (8 mL) was added LiOH (230 mg, 0.0055 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (670 mg after lyophilization) as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:21]([N:18]1[CH2:19][CH2:20][CH:15]([N:3]([CH3:2])[C:4]([C:6]2[CH:14]=[CH:13][C:9]3=[N:10][O:11][N:12]=[C:8]3[CH:7]=2)=[O:5])[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 1 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.58 g, 1.9 mmol) was suspended in chloroform (50 ml), and acetic anhydride (2 ml) and triethylamine (4 ml), were added. After stirring for 1 h, the mixture was washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (2×100 ml) and the combined organics dried (MgSO4) and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform/methanol (50:45:5) to give a white solid after crystallization from ethyl acetate/MTBE/hexane (470 mg). Mp=173-175° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.0 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.0 Hz, 1H); 4.90-4.70 and 4.05-3.80 (m, 5H); 2.89 (sb, 3H); 2.13 (sb, 3H), 1.95-1.60 ppm (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]#[N:20]>O1CCCC1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:18][C:19]#[N:20])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
18.4 g of 4-benzylphenol was dissolved in 100 ml of anhydrous tetrahydrofuran and 4.0 g of sodium hydride (60 % oil dispersion) was gradually added to the solution with ice cooling :n nitrogen stream. The solution was stirred for 1 hour at room temperature and 12.0 g of bromoacetonitrile was added thereto under ice cooling, followed by refluxing with heating for 3 hours. After being left for cooling, the reaction mixture was concentrated under reduced pressure and to the residue was added 100 ml of water, followed by extracting twice with 100 ml of chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. The residue was chromatographed on a silica gel column (eluting solvent hexane : acetone=3 : 1 (v/v)) to obtain 19.1 g of (4-benzylphenoxy)acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.6 mmol) was combined with pyridine (50 mL) and heated to 50° C. Benzoyl chloride (0.22 g, 1.6 mmol) was added via a pipette. After 1 hour analysis by HPLC indicated that all of the starting material was gone and that several products had formed. The reaction mixture was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate. The organic layer was separated and then concentrated under vacuum. The residue was dissolved in dichloromethane and placed on a silica gel column. The column was eluted with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The 10% methanol in dichloromethane fractions were combined and concentrated under vacuum to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 174-175° C. 1H NMR (500 MHz, DMSO-d6) δ8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.50 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.32 (m, 2H), 2.91 (t, J=7.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.41 (sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H); MS (CI) m/e 416 (M+H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:25]3)[CH2:18][CH2:19]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
NaBH4 (2.64 g, 69.8 mmol) was added carefully in portions to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-[2-(methylsulfonyl)-ethyl]piperazine (9.9 g, 23.3 mmol), nickel(II)chloride hexahydrate (1.66 g, 7 mmol), MeOH (120 mL) and THF (60 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at rt overnight (˜16 h). The reaction mixture was concentrated onto silica gel and flash chromatography afforded the title compound of step B (6.24 g, 68%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.44 (m, 2H), 6.26 (dd, J=8.4, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.43-3.36 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.00 (s, 3H), 2.65 (t, J=6.8 Hz, 2H), 2.47-2.36 (m, 4H), 2.23-2.15 (m, 1H), 1.82-1.75 (m, 2H), 1.54-1.43 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[CH:8][C:7]=1[Cl:20])[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[Cl:20])[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)ccc1Cl
Solvent: CCO
Product: CCOC(=O)Cc1cc(O)ccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
(5-Benzyloxy-2-chloro-phenyl)-acetic acid ethyl ester (1.7 g, 5.6 mmol) was dissolved in EtOH (30 mL) and degassed with N2. 5% Palladium on carbon (1 g) was added, and the reaction was purged with H2 and then stirred under an H2 balloon at 50° C. overnight. The mixture was filtered and concentrated to give the desired product (1 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.C[O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16].CN(C=O)C>ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14](=[O:13])[C:15]([F:18])([F:17])[F:16])[CH2:7]2
Reactant: COC(=O)C(F)(F)F
Reactant: Oc1cccc2c1CCNC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N1CCc2c(O)cccc2C1)C(F)(F)F
Temperature: 25 °C

Procedure:
2.35 g (15.9 mmol) 5-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.92 mL (19.0 mmol) methyltrifluoroacetate and 15 mL DMF were mixed and stirred for over night at room temperature. The reaction mixture was diluted with dichloromethane, washed with water containing one drop of dil. hydrochloric acid and with aqueous sodium chloride. After drying over Na2SO4 and evaporation to dryness, the product was purified by silicagel chromatography (system C). Yield quantitative. 1H NMR (CDCl3, 400 MHz): 8.15 (1H, bd), 7.06 (1H, t, 8.1 Hz), 6.6-6.9 (2H, m), 4.75 (2H, ss), 3.86 (2H, m), 2.90 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])([O-])=[O:28].[Cs+].[Cs+]>CN(C=O)C>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:17]2[S:16][C:15]3[C:14](=[O:28])[C:13]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][NH:11][C:12]=4[C:19]=3[CH:18]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2n[nH]c3c2C(=O)c2sc(-c4ccc(N)nc4)cc2-3)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.18 g, 0.5 mmol) and Cs2CO3 (1.6 g, 5.0 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. Afterward, the mixture was poured into ice water, followed by aqueous wash, and evaporation of the solvent, which provided the corresponding 2-(6-Amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one as yellow solid in 92% yield.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[NH:50][CH:46]3[CH2:49][CH2:48][CH2:47]3)[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: NC1CCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and cyclobutylamine (6% yield after two steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:8]=2[NH:7][C:6]1=[O:19].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:40])=[CH:24][N:23]=1>>[CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:14]=[CH:15][C:16]([NH:18][C:22]3[N:27]=[C:26]([NH:28][C:29]4[C:30]([C:31](=[O:32])[NH:33][CH3:34])=[CH:35][CH:36]=[CH:37][C:38]=4[F:39])[C:25]([Cl:40])=[CH:24][N:23]=3)=[CH:17][C:8]=2[NH:7][C:6]1=[O:19]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)OC)CC3(C)C)ncc1Cl

Procedure:
{8-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl}-carbamic acid methyl ester was prepared from (8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-carbamic acid methyl ester and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1d. Title compound was isolated as a pale yellow solid (30 mg, 19%) LCMS 558 (M+H), HNMR (DMSO) 9.51 (s, 1H), 9.39 (s, 1H), 9.34 (s, 1H), 8.51 (d, 1H), 8.19 (s, 1H), 7.49-7.46 (m, 2H), 7.39-7.25 (m, 3H), 7.15 (s, 1H), 7.09 (m, 1H), 3.93-3.90 (m, 1H), 3.50 (s, 3H), 2.74 (d, J=3.8 Hz, 3H), 2.09-2.06 (m, 1H), 1.95-1.89 (m, 1H), 1.32 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37](Cl)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+].[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64]>CN(C)C=O.C(O)C>[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64].[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nc2ccc(Cl)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)NC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
1.56 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.50 g of N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester were dissolved in 20 ml of N,N-dimethylformamide; 1.65 ml of N-ethyldiisopropylamine was added, followed by stirring at 70° C. for 16 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; 880 mg of the oily substance obtained was dissolved in 5 ml of ethanol, followed by the addition of 170 mg of fumaric acid and concentration; the resulting concentrate was powdered by the addition of ethyl ether, washed with ethyl ether, collected by filtration and dried to yield 931 mg of the title compound.