Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: C1COCCN1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCOCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 79 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with morpholine (1 mL) in MeOH (3 mL) under reflux to give the desired product (61 mg, 79%, Z/E=1/2) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.13 & 7.09 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.83 & 6.80 (d, J=8.6 Hz, 2H), 6.72 & 6.69 (d, J=8.6 Hz, 2H), 6.45 (s, 1H), 6.43 (d, J=8.8 Hz, 2H), 4.12 & 3.94 (t, J=5.6 Hz, 2H), 3.76 & 3.71 (t, J=4.8 Hz, 4H), 2.83 & 2.71 (t, J=5.6 Hz, 2H), 2.61 & 2.52 (t, J=4.4 Hz, 4H), 2.49 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H); m/z=504[M+1]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g, 2.53 mmol) and propionaldehyde (1 ml, 13.86 mmol) in 1,2-dichloroethane (30 ml) was added sodium triacetoxyborohydride (1.9 g, 8.96 mmol) at room temperature, and the mixture was stirred for 24 hours. To the reaction system was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in THF (50 ml) and methanol (50 ml), and to the solution was added 1N sodium hydroxide solution. After heating to reflux for 1 hour, the mixture was concentrated under reduced pressure. To the residue was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.895 g) as yellow crystals.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[C:9]([Cl:30])[CH:8]=1)C.Cl.C(O)(=O)C>O>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:9]([Cl:30])=[CH:8][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:12][C:11]=2[Cl:13])=[CH:21][CH:22]=1
Reactant: CCOC(COc1cc(Cl)c(OCCCCOc2ccc(C(F)(F)F)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=CCOc1cc(Cl)c(OCCCCOc2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
4-(4-(4-(Trifluoromethyl)phenoxy)butyloxy)-3,5-dichlorophenoxyacetaldehyde diethylacetal (manufactured in Production Example 1 of intermediate described hereinafter) (1.0 g) was added dropwise to a mixed solution of 1 ml of hydrochloric acid and 9 ml of acetic acid with stirring at room temperature. After stirring at room temperature for 20 minutes, the reaction solution was poured into iced water and extracted twice with 100 ml of diethyl ether. The ether layers were combined, washed with water, washed twice with aqueous 5% sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain 0.7 g of 4-(4-(4-(trifluoromethyl)phenoxy)butyloxy)-3,5-dichlorophenoxyacetaldehyde as a crude product.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:7]([OH:16])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:15][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: CCCOC(=O)c1cc(C(C)=O)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc(C(C)=O)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
Propyl 5-acetylsalicylate (202 mg), 4-chloro-6,7-dimethoxyquinoline (101 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (35 mg, yield 9%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[BrH:13].[CH2:14]=O>>[BrH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Br:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: C=O
Agent: Br
Product: NC(C(=O)O)c1ccc(O)c(CBr)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (0.6 mole) in a minimum amount of concentrated hydrobromic acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen bromide gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes. The title compound is collected and washed with ether and acetone.
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:3][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C([Li])CCC.[Cl-].[CH3:26][C:27]([NH:30][SiH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C1COCC1>[CH3:13][C:2]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:1])[CH2:3][C:4]1[CH:12]([Si:31]([CH3:33])([CH3:32])[NH:30][C:27]([CH3:29])([CH3:28])[CH3:26])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)(CC1=Cc2ccccc2C1)c1ccccc1
Reactant: C[SiH](C)NC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C(CC(C)(C)c2ccccc2)=Cc2ccccc21
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a mixture of 2-(2-methyl-2-phenyl propan-1-yl)indene (1.55 g, 6.2 mmol) in 50 mL of hexanes were added 4.0 mL of butyl lithium (1.6 M hexane; 1.02 equiv.). The mixture was stirred overnight, filtered, the solid was washed with hexanes and dried, recovering 1.05g (66 percent of indenyl lithium salt) of very pale yellowish solid. The solid was dissolved in THF and a solution of N-(1,1-dimethylethyl)dimethylsilanamine chloride (0.7 g, 1.03 equiv.; 4.2 mmol) in 20 mL of THF was added and the solution was stirred overnight. The volatiles were pumped off, the residue extracted with hexane, filtered and the filtrate was then dried in vacuo to give 1.5 g (96 percent) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:21])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)N3CCCCC3)ccc2n1C

Procedure:
An amount of 0.5 g (1.4 m mole) of 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5yloxy]-2-methyl-propanoic acid was dissolved in 25 ml of tetrahydrofurane and heated for four hours with 0.24 g (1.4 m mole) of N,N'-carbonyldiimidazole on a steam bath. Subsequently, 0.24 g (2.8 m mole) of piperidine were added, and the mixture was refluxed for 12 hours. After evaporation the residue was mixed with dilute hydrochloric acid and extracted with ether. The evaporated ether residue was purified by column chromatography with toluene/ethyl acetate (8:2) on silicagel.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[S:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.CS(O[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[N:31]=1)(=O)=O>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[S:19][C:18](=[O:20])[N:17]([CH2:29][C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([C:37]([F:39])([F:38])[F:40])[N:31]=3)[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@@H]1NC(=O)S[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCc1nc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC(=O)N1Cc1nc(C(F)(F)F)ccc1Cl
Temperature: -10 °C
Reaction time: 5 h

Procedure:
A solution of NaH (18 mg, 0.46 mmol) in THF (2.0 ml) was cooled to −20° C. To this was added a solution of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one (100 mg, 0.304 mmol) in THF (1.0 ml) dropwise at the same temperature. The reaction was allowed to warm to −10° C. over 1 hour. A solution of (3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (106 mg, 0.364 mmol) in THF (1.0 ml) was added via syringe. Stirring of the reaction was continued at −10° C. for 5 hours. The reaction was quenched by addition of ice water and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The compound was purified by column chromatography to yield (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-4-methylthiazolidin-2-one. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.2 Hz, 1H); 7.89 (s, 1H); 7.85 (s, 2H); 7.64 (d, J=8.3 Hz, 1H); 5.36 (d, J=17.5 Hz, 1H); 5.24 (d, J=6.9 Hz, 1H); 4.54-4.55 (m, 1H); 4.37 (d, J=17.5 Hz, 1H); 0.99 (d, J=6.6 Hz, 4H).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([C:32]2[CH:37]=[C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[O:39])[CH:35]=[CH:34][C:33]=2[CH3:48])[C:16]2[CH2:21][NH:20][C:19](=[O:22])[N:18]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:17]=2[N:31]=1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([F:30])[C:23]=1[N:18]1[C:17]2[N:31]=[C:13]([NH:12][CH2:11][CH2:10][NH:6][CH3:5])[N:14]=[C:15]([C:32]3[CH:37]=[C:36]([CH:35]=[CH:34][C:33]=3[CH3:48])[C:38]([NH:40][C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)=[O:39])[C:16]=2[CH2:21][NH:20][C:19]1=[O:22]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(CC(C)(C)C)C(=O)[O-])nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of 1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(5-{[(4-fluorophenyl)amino]carbonyl}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate (20 mg, 0.030 mmol) in DCM (5 mL) was added TFA (0.06 mL). The reaction mixture was stirred at room temperature overnight, quenched with triethylamine (0.2 mL) at −78° C. The residue was mixed with H2O (5.0 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3×15 mL). The combined organic phases were washed with saturated aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (90% CH2Cl2/7% MeOH/3% NH4OH) then afforded the title compound (11 mg, 65%). LC-MS (ES) m/z 562 (M+H)+; 1H-NMR(MeOD) δ 2.27 (s, 3H), 2.34 (s, 3H), 2.57 (m, 2H), 3.26 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 7.97 (d, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ncccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ncccc2n1-c1ccccc1
Temperature: 90 °C
Yield: 36.2 %

Procedure:
A mixture of (S)-1-(1-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethylamine (330 mg, 1.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (460 mg, 1.94 mmol) and DIPEA (440 μL, 2.49 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) and then crystallised from EtOAc and MeOH to afford 199 as a white solid (178 mg, 36%). LCMS (Method K): RT 2.72 min [M+H]+ 357.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.42 (1H, dd, J=4.73, 1.53 Hz), 8.20-7.94 (3H, m), 7.68 (2H, d, J=7.55 Hz), 7.63-7.48 (4H, m), 7.23 (1H, dd, J=8.06, 4.74 Hz), 5.51 (1H, br s), 1.60 (3H, d, J=6.85 Hz)
Reaction SMILES: [C:1]([CH2:5][NH:6][NH2:7])([F:4])([F:3])[F:2].C([O:10][C:11]([C:13]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18](=O)[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=O)C.C(O)(=O)C>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:15]1[CH2:16][CH2:17][C:18]2=[N:7][N:6]([CH2:5][C:1]([F:4])([F:3])[F:2])[C:11](=[O:10])[C:13]2([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)C1(Cc2ccccn2)CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Temperature: 70 °C
Yield: 110.6 %

Procedure:
A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3×1200 mL). To a solution of the product from step A (600 g, 1.655 mol) in toluene (900 mL) was first added the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was heated at about 70° C. for about 2 hours, then another toluene extraction of 70% aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added. The reaction mixture was heated at about 80° C. for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO3 (2 L). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water afforded the desired product as a white solid (609.5 g). 1H-NMR (CDCl3) δ 1.50 (s, 9H), 2.53 (d, 1H), 2.70 (br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46 (br s, 1H), 4.63 (br s, 1H), 7.06 (m, 2H), 7.51 (m, 1H), 8.34 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:24]=1.C[Al](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:24]=2)=[O:13])[N:3]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1
Reactant: Nc1cc2ccccc2cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 120 °C
Yield: 31.1 %

Procedure:
To a stirred solution of 3-aminoisoquinoline (75 mg, 0.52 mmol) and 2-({2-[(morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester (149 mg, 0.40 mmol) in DCE (6 mL) at 0° C., under argon, was added trimethylaluminium (2M in toluene, 0.4 mL, 0.8 mmol). The reaction was heated at 120° C. (bath temperature) for 3 hours. On cooling the reaction was diluted with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash NH2 (Separtis) (Eluant: EtOAc) to give morpholine-4-carboxylic acid (4-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (60 mg, 32%) as a resin; 1H-NMR (300 MHz, d6-DMSO) 10.69 (1H, s), 9.21 (1H, s), 9.18 (1H, s), 8.60 (1H, s), 8.16-8.20 (2H, m), 8.10 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.82 (1H, d), 7.75 (1H, t), 7.57 (1H, t), 7.28 (1H, t), 6.98 (1H, d), 6.63 (1H, t), 6.58 (1H, d), 4.48 (2H, d), 3.55-3.59 (4H, m), 3.41-3.45 (4H, m); m/z (ES+) 483 [M+H]+, 242.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (1.42 g, 11.5 mmol), 2,4-dichloro-6-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol), DIPEA (4.05 mL, 23.0 mmol), and anhydrous EtOH (35 mL) was stirred at 70° C. under N2 for 22 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and the organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration with DCM afforded 1.80 g (51.5%) of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidin-4-amine (186) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 12.35 (br d, J=30.2 Hz, 1H), 10.97 (s, 1H), 8.14 (s, 0.50H, rotamer), 7.13 (s, 0.50H, rotamer), 6.38 (s, 0.50H, rotamer), 5.73 (s, 0.50H, rotamer), 1.91 (s, 1H), 0.98-0.90 (m, 2H), 0.70 (q, J=5.5 Hz, 2H); MS (ESI) m/z=304.2/306.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([O:24][CH3:25])[C:18](OCCC)=O.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([O:24][CH3:25])[C:16](=[O:15])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: CCCOC(=O)C(=CO)OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cnc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Four (4) grams of the thus obtained 2-amino-5-benzylthio-1,3,4-thiadiazole, 3.2 g of propyl 3-hydroxy-2-methoxy-propenoate and 11 g of polyphosphoric acid were heated to 135° C. and stirred for 20 minutes. After cooling, chloroform and water were added thereto, extraction was carried out. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was washed with an ethanol/hexane mixture and 5.1 g of 2-benzylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 93%. The compound was recrystallized from ethanol. m.p. 145°-147° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][CH2:9][CH2:10][CH:11]([OH:25])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[O:13]>C(N(CC)CC)C>[C:1]([NH:5][C:6]([O:25][CH:11]([CH2:10][CH2:9][Cl:8])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)OC(CCCl)C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 40.1 %

Procedure:
t-Butylisocyanate (0.093 g) and triethylamine (0.095 g) were added successively to a stirred solution of 4-chloro-2-hydroxy-N(3-trifluoromethylphenyl)butanamide (0.24 g, prepared as described in Example 10, Step 1a above). After a day further aliquots of t-butylisocyanate and triethylamine were added. After a further twenty hours, the mixture was evaporated under reduced pressure and the residue chromatographed under reduced pressure to give the title compound (0.13 g, m.p. 115°-116° C.). NMR (CDCl3): δ 1.4(9H,s); 2.4(2H,m); 3.65(1H,t); 5.0(1H,bs); 5.35(1H,t); 7.35(2H,m); 7.7(1H,d); 7.8(1H,s); 8.6(1H,bs). MS: MH+ 381, 383.
Reaction SMILES: [ClH:1].Cl.Cl.C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:20][CH:19]([N:21]([CH3:23])[CH3:22])[CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1.O>CC(O)C.[C].[Pd]>[ClH:1].[ClH:1].[ClH:1].[CH3:22][N:21]([CH3:23])[CH:19]1[CH2:18][N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:20]1
Reactant: CN(C)C1CN(C2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN(C)C1CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 297.8 %

Procedure:
After adding 10% palladium-carbon (5.0 g) to a solution of the crude N-[1-(1-benzylpiperidin-4-yl)azetidin-3-yl]-N,N-dimethylamine trihydrochloride (14.1 g) in 2-propanol (380 ml)-water (380 ml), the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The catalyst was then filtered. The filtrate was concentrated under reduced pressure to provide a crude product of the title compound (10.7 g) as colorless crystals.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[S:6]1[C:10]2[C:11]3[CH:17]=[N:16][NH:15][C:12]=3[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:18].S(=O)(=O)(O)O>>[N+:1]([C:14]1[C:9]2[N:8]=[C:7]([NH2:18])[S:6][C:10]=2[C:11]2[CH:17]=[N:16][NH:15][C:12]=2[CH:13]=1)([O-:4])=[O:2]
Reactant: Nc1nc2ccc3[nH]ncc3c2s1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1nc2c([N+](=O)[O-])cc3[nH]ncc3c2s1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under ice-cooling, 184 mg (2.17 mmol) of sodium nitrate was added to a mixture of 191 mg (1.01 mmol) of 6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine and 3 ml of concentrated sulfuric acid, and the mixture was stirred for 0.5 hours. The reaction mixture was poured onto ice, and the precipitated solid was collected by filtration, and then washed with water and methanol to give 160 mg (yield: 68%) of 4-nitro-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine.