Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[CH3:13][C:14]([CH3:25])([CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH:15]=O.C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)C>[CH3:13][C:14]([CH3:25])([C:15]#[CH:1])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C=O)COC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#CC(C)(C)COC1CCCCO1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (486 mg, 2.54 mmol) was added to a stirred suspension of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (315 mg, 1.69 mmol) and K2CO3 (700 mg, 5.07 mmol) in methanol (20.0 mL) at room temperature. After overnight stirring, the reaction was diluted with diethyl ether, washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated to provide a crude oil. Purification by flash column chromatography on silica gel using 20% ethyl ether in hexanes provided 2-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-pyran (147 mg, 48%) as a pale liquid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 2-bromoethylbenzene (10.0 g; 54 mmol) in 16 ml of chloroform placed at a temperature of 0° C. was added dropwise a solution of chlorosulfonic acid (162 mmol, 18.87 g; 10.82 ml) in 11 ml of chloroform. After 15 minutes at 0° C., the reaction was maintained at room temperature for 3 hours. The reaction mixture was poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated off to give 12.34 g of crude product, which was purified by chromatography on a column of silica, eluting with chloroform (76% yield). The product obtained was used for the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Cc1cccnc1N
Product: Cc1cccnc1-n1c(C)nc2ccccc2c1=O

Procedure:
Acetanthranil (4.5 g, 0.028 mole) was mixed with 2-amino-3-picoline (2.7 g, 0.025 mole) and the mixture was heated in an erlenmeyer flask, first at low heat and then at high heat over an open flame. The product was washed with ether and recrystallized from ethanol/water mixture. The yield was 3.7 g (58%), mp 135°-137° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH2:25]([Sn](CCCC)(CCCC)C#CC)[CH2:26][CH2:27]C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:25]#[C:26][CH3:27])=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 96 °C
Reaction time: 40 h
Yield: 76.1 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (Example 1) (120 mg, 0.31 mmol) and tributyl(1-propynyl)tin (140 μL, 0.46 mmol) were stirred in dioxane (5 mL) in a flask purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) was added, and the solution stirred at 96° C. for 40 h. Concentration in vacuo and purification by silica gel chromatography (16% MeOH/CHCl3) gave 82 mg (76%) of the title compound as a clear oil. 1H NMR (400 MHz, MeOD-d4): δ7.82 (s, 1H), 7.64 (d, 1H, 7.6 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.36 (t, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 5.30 (s, 2H), 3.40-3.48 (m, 1H), 3.21-3.30 (m, 1H), 2.78-2.89 (m, 2H), 2.58-2.66 (m, 1H), 1.91 (s, 3H), 1.85-1.93 (m, 1H), 1.52-1.74 (m, 2H), 1.18-1.27 (m, 1H). MS (ES) [m+H] calc'd for C20H21N5O, 348; found 348.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:12][CH:13]1[N:19]=[C:18]([CH3:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[N:15]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:14]1=[O:32]>CC#N>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([CH3:20])=[N:19]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=NC(N)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: CC#N
Product: CC1=NC(NC(=O)Nc2cccc(C#N)c2)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
3-Cyanophenyl isocyanate (278 mg) was added to a solution of 3-amino-2,3-dihydro-1-(3,3,-dimethyl-2-oxo-butyl)-5-methyl-2-oxo-1H-1,4-benzodiazepine (500 mg) in dry MeCN (13 ml) at 23° under nitrogen. After 30 min the resulting thick slurry was stirred with DE (5 ml) filtered and the filtercake washed with EA and DE then dried in vacuo at 50° to give the title compound (571 mg) as a white solid, m.p. 246°-7°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+].[C:21]([C:23]1[C:24]([O:36][CH3:37])=[C:25]([C:33](Cl)=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)#[N:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][N:11]([CH3:12])[C:33]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]=[C:23]([C:21]#[N:22])[C:24]=2[O:36][CH3:37])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)Cl
Reactant: CNC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-[2-(S)-(3,4-dichlorophenyl)4-hydroxybutyl]-N-methylamine (Miller, SC; WO 9512577) in DCM was combined with 10% aqueous sodium bicarbonate solution. The mixture was cooled to 0° C. and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight at room temperature, the organic phase was concentrated and purified by column chromatography to afford N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide. 1H NMR (300 MHz, DMSO-d6) d 8.67-8.58 (m), 8.07-8.00 (m), 7.72-7.65 (m), 7.64-7.43 (m 7.42-7.34 (m), 7.02-7.01 (m), 6.98-6.87 (d), 6.77-6.74 (d), 6.31-6.28 (d), 4.55-4.52 (t), 4.35-4.34 (t), 4.03-3.92 (m), 3.78-3.72 (m), 3.68 (s), 3.45-3.37 (m), 3.29-2.89 (m), 2.73 (s), 2.59-2.49 (m), 1.91-1.78 (m), 1.58-1.46 (m); MS APCI, m/z=457 (M+). (g) N-[2-(S)-(3,4-Dichlorophenyl)-3-carboxypropyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide According to the procedure of Corey, E J and Schmidt, G, Tetr. Lett., 1979, 399, a solution of pyridinium dichromate (4.5 g) was added to a solution of N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamine(1.5 g) in DMF (20 mL) and stirred for 4 h. After filtration, dilution with ethyl acetate, and aqueous extraction of the filtrate, the product was purified by flash chromatography (80%). 1H NMR (300 MHz, DMSO-d6) d 12.28 (s), 8.66-8.62 (m), 8.09-7.95 (m), 7.78-7.76 (m), 7.72-7.56 (m), 7.52-7.45 (m), 7.40-7.30 (m), 7.11-7.10 (d), 7.04 (s), 7.01 (s), 6.87-6.84 (d), 4.53-4.45 (t), 3.94 (s), 3.92 (s), 3.68 (s), 3.44-3.27 (m), 3.11 (s), 3.02 (s), 2.76-2.73 (m), 2.62 (s), 2.55-2.38 (m); MS APCI, m/z=471 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[NH2:17])=[O:5])C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:4](=[O:5])[C:6]3[O:10][N:9]=[C:8]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:17]=[C:26]2[C:27]2[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1N
Reactant: CC(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)noc3c(=O)n2-c2ccc(Cl)cc2)cc1

Procedure:
6-(4-Chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one is prepared as described in Example 2, using 4-amino-3-phenyl-isoxazole-5-carboxylic acid ethyl ester from step C instead of ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate, and N-(4-chloro-phenyl)-4-isopropyl-benzamide instead of N-(4 bromo-phenyl)-4-methyl-benzamide; 1H NMR (CDCl3, 400 MHz) δ 8.42 (dd, 2H), 7.53 (m, 3H), 7.34 (d, 2H), 7.25 (d, 2H), 7.12 (m, 4H), 2.87 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated for C26H20ClN3O2 (M+H+) 442.1. Found 442.1.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].B(F)(F)F.CCOCC.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Cl
Reactant: Oc1cccc(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
Combine resorcinol (1010 g, 9.17 mol) in boron trifluoride etherate (1.9 L, 15.0 mol) and mechanically stir in a 12-L Morton flask at room temperature. Treat mixture with isobutyryl chloride (880 mL, 8.37 mol), neat, over a 3 hour period via addition funnel, then stir overnight at room temperature. Pour the cooled oil into ˜10 kg of cracked ice and extract twice with ethyl ether (5 L total). Wash organic layers with water, saturated sodium chloride solution, dry with magnesium sulfate, filter, and evaporate filtrate to provide the title compound (1636 g, quantitative yield) as a reddish oil. HPLC Rt=4.29 min; 1H NMR (CDCl3) δ 13.03 (s, 1H), 7.69 (d, J=12.0 Hz, 1H), 6.4 (m, 2H), 3.51 (hept, J=8.0 Hz, 1H), 1.23 (d, J=8.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH:11]([C@@H:19]([C:23]1[CH:36]=[CH:35][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[N:38]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([C:10]2[C:3]3[C:2](=[C:7]([F:8])[CH:6]=[C:5]([CH3:9])[CH:4]=3)[NH:1][N:38]=2)[C@@H:19]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:35][CH:36]=2)[CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(C(=O)c1cc(C)cc(F)c1N)c1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@H](c1ccc(Cl)cc1)c1n[nH]c2c(F)cc(C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step A (74 mg, 0.14 mmol) was suspended in concentrated HCl (1 mL) then cooled to 0° C. To the stirred suspension was added a solution of NaNO2 (7.5 mg, 0.11 mmol) in water, then the mixture was stirred for 30 minutes. Solid SnCl2 (47 mg, 0.25 mmol) was added, then the mixture was stirred for another 30 minutes. Ice was added, then the mixture was extracted with EtOAc. The organic phase was washed with water then saturated NaCl(aq), dried over Na2SO4, filtered, then concentrated. The residue was purified by reverse phase HPLC eluting with 10-70% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=7.9 Hz, 2H); 7.43 (d, J=8.1 Hz, 2H); 7.31 (d, J=8.2 Hz, 2H); 7.26 obs, 2H); 7.17 (s, 1H); 6.85-6.78 (m, 2H); 4.60 (d, J=11.6 Hz, 1H); 3.76-3.62 (m, 3H); 2.70 (t, J=5.6 Hz, 2H); 2.41 (s, 3H); 1.59-1.43 (m, 2H); 1.07-0.96 (m, 2H); 0.73 (t, J=7.3 Hz, 3H). LC1 2.36 min. (M+H)+ 522.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][NH:5][C:4](=[S:17])[NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39]I)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[C:41]([F:44])([F:43])[F:42]>CC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][S:17][C:4]3[NH:5][CH:6]=[C:7]([CH2:8][C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[C:2](=[O:1])[N:3]=3)=[CH:36][CH:37]=2)=[CH:27][C:26]=1[C:41]([F:42])([F:43])[F:44]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Reactant: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 604.4 %

Procedure:
To a suspension of 4-[(4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]benzonitrile (40 mg, 0.164 mmol) and K2CO3 (25 mg, 0.181 mmol) in Acetone (5 mL), which was stirred at room temperature for 5 min was added 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (42 mg, 0.098 mmol) under argon. The mixture was heated with a microwave reactor at 80° C. for 45 min. Purification via MDAP then afforded the title compound (321 mg, 37.4% yield). LCMS: rt=4.07 min, [M+H+]=542
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[CH2:22]([C:25]1[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=1)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH2:22][CH2:23][CH3:24])[S:26][CH:27]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CCCc1nc(CN)cs1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: CCCc1nc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-76-7) and 2-propyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 442.134 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH3:10][S:9][C:4]1[N:5]=[C:6]([N:13]([CH2:11][CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:7]=[C:2]([N:13]([CH2:11][CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:3]=1
Reactant: CCNc1cccc(O)c1
Reactant: CSc1nc(Cl)cc(Cl)n1
Product: CCN(c1cccc(O)c1)c1cc(N(CC)c2cccc(O)c2)nc(SC)n1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylthio-pyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-ethylaminophenol instead of the 3-aminophenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:31][C:30]([Cl:33])=[CH:29]C=1)=O>CO.O>[Cl:33][C:30]1[CH:31]=[CH:3][C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:29]=1
Reactant: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the reactions described in examples 1.5 and 1.7 trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester (example 3.2) was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 354 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl.CN(C1C=CN=CC=1)C>[C:21](=[O:22])([O:23][CH3:24])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[Cl:12]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 mL) was added Et3N (50.5 g, 0.50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at 0° C. The reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction mixture was washed with H2O and the organic layer was dried over Na2SO4 and concentrated to give 4-tert-butyl-2-chlorophenyl methyl carbonate (56.6 g, 92%), which was used directly in the next step.
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)c2ccccc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCl)c2ccccc2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-hydroxymethyl-2-methyl quinoline (7.0 g, 40 mmol) was dissolved in chloroform (150 mL) and cooled to 0° C., thionyl chloride (15.0 mL) was added slowly at this temperature and then the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in-vacuo and the residue was titureted with ethyl acetate/ethyl ether to provide 9.0 g (100%) of 4-chloromethyl-2-methyl quinoline as an HCl salt. MS (ESI): 191.9 (M+H+).
Reaction SMILES: NC(N)=O.C[O:6][C:7](=[O:24])[CH2:8][C:9]1[C:10]([CH3:23])=[N:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:13]=1[CH3:14].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([NH:32][C:33](=[O:34])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:13]([CH3:14])=[C:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10]([CH3:23])=[N:11]2)=[CH:17][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Agent: NC(N)=O
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)NCc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Urea formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 160 mg, 0.59 mmol) in dichloromethane (2 mL) was added benzyl isocyanate (94 μL, 0.76 mmol). The reaction mixture was stirred for 1 h at room temperature. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (1 mL) and treated with aqueous LiOH solution (1 M, 1.5 mL). After 18 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[CH:21]1([CH:24]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[CH2:25][C:26]([O:28]C)=[O:27])[CH2:23][CH2:22]1>>[CH:21]1([CH:24]([C:30]2[CH:31]=[CH:32][C:33]([O:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=3)=[CH:34][CH:35]=2)[CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:22]1
Reactant: COC(=O)CC(c1ccc(O)cc1)C1CC1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)C3CC3)cc2)cc1)c1ccccc1
Yield: 22.9 %

Procedure:
Compound 87 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.8146 mmol) and methyl 3-cyclopropyl-3-(4-hydroxyphenyl)propanoate (0.2 g, 0.9082 mmol) by following the procedure described in scheme 30 (0.04 g, yield: 22.90%); Purity: 98.07%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: NC(=O)c1cc(-c2cc(Cl)ccc2Cl)sc1N
Reactant: COCc1cccc(Br)n1
Product: COCc1cccc(Nc2sc(-c3cc(Cl)ccc3Cl)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-bromo-6-(methoxymethyl)pyridine (105 mg, 0.520 mmol) (for preparation, see Journal of Organic Chemistry 1993, 58, 4389-97) and 2-amino-5-(2,5-dichlorophenyl)thiophene-3-carboxamide (152 mg, 0.530 mmol) as starting materials.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][NH:30][CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[N:30]([CH3:29])[CH:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: CNC1CCN(C)C1
Product: CN1CCC(N(C)C(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and N,1-dimethyl-pyrrolidin-3-ylamine (10 mg, 85 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (12 mg, 35%).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:25][C:26]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:26]=2[F:25])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)c2cccc(C(F)(F)F)c2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To the mixture of Example 6B (293 mg, 1.129 mmol) and triethylamine (0.472 mL, 3.39 mmol) in CH2Cl2 (5 mL) cooled with an ice-bath was added 2-fluoro-3-(trifluoromethyl)benzoyl chloride (307 mg, 1.355 mmol) in one portion. The mixture was stirred at ambient temperature for 2 h, the solvent removed under reduced pressure and the residue purified by flash chromatography (silica gel, 10-60% EtOAc/hexane) to yield 420 mg (90%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.58-1.97 (m, 4H), 3.55-3.78 (m, 2H), 4.06-4.20 (m, 3H), 6.30 (s, 1H), 7.57 (t, J=7.80 Hz, 1H), 8.01 (q, J=8.02 Hz, 2H), 10.42 (s, 1H); MS (ESI) m/z 414 (M+H)+, 412 (M−H)−.