Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:11][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[CH:1]=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a solution of m-anisaldehyde (55.4 g, 0.41 mol) in DMF (400 mL) was added a solution of N-bromosuccinimide (124.0 g, 0.69 mol) dropwise at room temperature. After the addition, the reaction solution was stirred at room temperature for 12 h, then poured into a mixture of ice and water and stirred for 10 min. The precipitate was collected by filtration and dissolved in ethyl acetate. The resulting solution was washed with water (2×) and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 19 (76.4 g, 87%) as an off-white solid: 1H NMR (CDCl3, 500 MHz) δ 10.32 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.42 (d, J=3.5 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCI
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of triphenylphosphine (40 g, 153 mmol) and imidazole (10.4 g, 153 mmol) in CH2Cl2 (375 mL) at RT, is added iodine (40.8 g, 160.6 mmol) portionwise. To this solution is added (2-hydroxyethyl)-carbamic acid tert-butyl ester (24.2 g, 150 mmol) in CH2Cl2 (75 mL) dropwise and the mixture allowed to stir at RT for 14 h. The mixture is then filtered and the filtrate concentrated to a crude red oil, which is partitioned between ether and sat. sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 500 mL and then filtered through a plug of silica, eluting with hexane. Evaporation of solvent affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([O:11][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C=CCc1c(O)ccc([N+](=O)[O-])c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1c(OC(C)=O)ccc([N+](=O)[O-])c1C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-methyl-4-nitro-2-(2-propenyl)-phenol (5.19 g, 26.9 mmol) in dichloromethane (200 ml) at 0° was added triethylamine (5.43 g, 53.8 mmol) and acetic anhydride (3.29 g, 32.3 mmol). After 30 min, the reaction mixture was evaporated to a residue which was purified by chromatography (silica, 2% to 10% ethyl acetate in hexane) to give an orange oil (4.80 g, 76%).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[CH:20]=[CH:21][S:22][C:10]=12.[OH-].[K+]>O>[CH3:5][N:12]1[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:8])[C:10]2[S:22][CH:21]=[CH:20][C:11]1=2
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl sulphate (3.9 ml) was added to a stirred solution of ethyl 7-hydroxythieno[3,2-b]-pyridine-6-carboxylate (4.63 g) and potassium hydroxide (3.5 g) in water (50 ml) at 0°-5°. More water (20 ml) was added and the mixture was stirred at ambient temperature for 24 hours. The solid product was collected by filtration, washed with water and dried to give the novel compound ethyl 4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 122°-128°.
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC.C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OC(C)C)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH:20]([C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1)=[CH2:21]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: C=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
DMF (30 mL) is added to 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (1.62 g, 4.18 mmol) (Example 2b), tributylvinyltin (2.40 g, 8.36 mmol), Pd2 dba3.CHCl3 (0.087 g, 0.084 mmol) and triphenylphosphine (0.089 g, 0.334 mmol) under nitrogen. The mixture is heated to 90° C., to give a clear tan solution. After 3 h, the mixture is cooled down, diluted with isopropyl acetate and washed twice with water and brine. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. The residue is purified by silica gel flash chromatography (10% wt silica gel/KF, elution with dichloromethane-methanol, 49:1 to 24:1) to give 4-(5-vinyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a yellow solid; MS (ESI) m/z 269.2 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.20 (s, 3 H), 1.51 (s, 3 H), 5.42 (br. s, 1 H), 5.69 (s, 1 H), 5.81 (br. s, 1 H), 6.95 (br. s, 1 H), 7.14 (br. s, 1H), 7.21 (s, 1 H), 7.42 (d, J=7.6 Hz, 1 H), 7.58-7.69 (m, 1 H), 7.70-7.80 (m, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:34]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)(=[O:36])[CH3:35]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol), triethylamine (0.32 ml) and catalytic amount of 4-Dimethylaminopyridine in 6.0 mL of CH2Cl2 was added a solution of acetyl chloride (0.068 ml, 0.864 mmol) in 1.0 mL of CH2Cl2. The reaction stirred at room temperature for 4 h and washed with H2O, brine, dried over MgSO4, filtered through a pad of silica gel and concentrated to provide 0.242 g (100%) of the desired product as a colorless gum. Electrospray Mass Spec: 422.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
4-Nitrophenol (8 gm, 56 mmol) in 100 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (6.2 g, 61 mmol) followed by the dropwise addition of bromoisobutyryl bromide (14.1 g, 61 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 16 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 13.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>C(OC)(C)(C)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: COC(C)(C)C
Solvent: C1CCCCC1
Solvent: O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in methyl tert-butyl ether (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The methyl tert-butyl ether was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 20 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.4 gm of maraviroc amorphous form.
Reaction SMILES: [CH2:1](O[CH:4]=[C:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])[CH3:2].[NH2:16][C:17]1[C:22]([OH:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][CH:18]=1.[CH3:26][CH2:27]CCCCC>>[CH2:1]([N:16]([CH2:26][CH3:27])[C:17]1[CH:18]=[CH:19][C:20]([F:25])=[C:21]([F:24])[C:22]=1[OH:23])[CH3:2].[CH2:4]=[C:5]([C:11]([O-:13])=[O:12])[C:6]([O-:8])=[O:7]
Reactant: Nc1ccc(F)c(F)c1O
Reactant: CCCCCCC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: C=C(C(=O)[O-])C(=O)[O-]
Product: CCN(CC)c1ccc(F)c(F)c1O
Temperature: 25 °C
Yield: 81 %

Procedure:
13.44 ml (66.34 mmol) of diethyl ethoxymethylenmalonate of are added to a solution of 9.6 g (66.34 mmol) of 3,4-difluoro-2-hydroxy-aniline [3] in 50 ml of n-heptane. The reaction mixture is reflux heated for 1 hour and then cooled at room temperature until a precipitate is obtained which is filtered at vacuum and washed with 20 ml of n-heptane. 17.5 g (81%) of diethyl (3,4-difluoro-2-hydroxyaniline)-methylenmalonate [4] are obtained and it does not need to be subject to a subsequent purification treatment.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10](=O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc2cccnc2n1

Procedure:
A solution of 10-4 (10 g, 53.4 mmol), 2-amino-3-formylpyridine 1-3 (7.2 g, 64 mmol), 20% aq. KOH (1 mL), and ethanol (200 mL) was heated at reflux for 3 h. Evaporation of the solvents and flash chromatography (silica, 70 CHCl3/28 EtOAc/2 MeOH) gave 10-5 as a solid.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=C3)C=C[CH:2]=1.CC(C)([O-])C.[Na+].CCCCCCCCCCCC.I[C:34]1[CH:35]=[C:36]([CH3:41])[CH:37]=[C:38]([CH3:40])[CH:39]=1.CNC1C=CC=CC=1>[Cu]I.O1CCOCC1>[CH3:40][C:38]1[CH:39]=[C:34]([N:1]([CH3:2])[C:14]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:13]=2)[CH:35]=[C:36]([CH3:41])[CH:37]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CNc1ccccc1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(N(C)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 469 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (10 mg, 0.0525 mmol, 5.0 mol %), 1,10-phenanthroline (20 mg, 0.111 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), evacuated and backfilled with argon. Dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol), N-methylaniline (135 μL, 1.25 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 50:1; 10 mL fractions). Fractions 7-11 provided 110 mg (50% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 2H), 7.05-6.94 (m, 3H), 6.72 (s, 2H), 6.68 (s, 1H), 3.33 (s, 3H), 2.31 (s, 6H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]
Reactant: CCOc1cc(CC(=O)O)ccc1C
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine an 3-ethoxy-4-methyl-phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: O=CO
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
A suspension of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (4.68 g, 8.76 mmol) in formic acid (150 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 15 minutes, dissolution occurred. After 11/4 hours, the reaction was diluted with water (1.2 L). The aqueous phase was extracted with ether (2×300 mL). The extracts were combined, dried with magnesium sulfate, and the ether was removed. The residue was suspended in water (150 mL) and filtered. The solid was washed with water (2×30 mL) and dried. The crude product was recrystallized in chloroform:hexane twice to yield the title compound as white needles (2.24 g, 53%), m.p. 167°-168.5° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-(trifluoromethoxy)aniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=3%). MS ISP (m/e): 456.3 (100) [(M+H)+].
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)CC1)OCc1ccccc1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: O=C(N[C@H]1CC[C@@H](CO)CC1)OCc1ccccc1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of cis-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure cis-4-benzyloxycarbonylaminocyclohexane-methanol as a colorless oil. TLC:rf (1:2 hept-EA)=0.45. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.07.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH3:14]>O1CCCC1>[NH2:14][S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: N
Reactant: COC(=O)c1ncsc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 28.9 g of methyl 5-(chlorosulfonyl)-4-thiazolecarboxylate in 150 ml tetrahydrofuran was cooled to 0° and 6.6 ml of liquid ammonia was added dropwise at 0°-10°. The suspension was allowed to warm to ambient temperature and stirred 1 hour. The reaction mixture was filtered, the ammonium chloride washed with tetrahydrofuran, and the solvent evaporated from the filtrate. The residual solid was slurried in hexane, collected and dried to give 25.0 g of the title compound, m.p. 138°-140°. IR: 301 and 3.1μ (SO2NH2) and 5.8μ (C=O).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:32])[CH:3]=1.[CH2:33]([S:35][CH2:36][CH2:37]O)[CH3:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:33]([S:35][CH2:36][CH2:37][O:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[CH3:34]
Reactant: CCSCCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(CCC(=O)OC(C)(C)C)cc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC(C)(C)C)cc3)c2)c(C)c1
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 3-{4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (1.69 g, 3.91 mmol), 2-(ethylthio)ethanol (0.46 mL, 4.30 mmol) and tributylphosphine (1.46 mL, 5.86 mmol) in tetrahydrofuran (33 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.48 g, 5.86 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 16 hrs., and an equivalent amount of the aforementioned reagents (2-(ethylthio)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) were added at the same temperature and the mixture was further stirred for 16 hrs. Diethyl ether was added to the reaction mixture and insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (1.40 g, yield 69%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1>>[Cl-:1].[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3]([CH2:2][N+:40]5([CH3:39])[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[O:4])[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN1CCN(C)CC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)C[N+]3(C)CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Product: [Cl-]

Procedure:
The title compound was prepared from 2-chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 80 mg, 0.149 mmol) and 1,4-dimethyl-piperazine (34 mg, 0.298 mmol) using a similar method to that employed for Example 18 (step 2) (38 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH2:13]1[O:15][CH2:14]1.Cl>CCOCC>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C1CO1
Agent: Cl
Solvent: CCOCC
Product: OCCc1ccc(OC(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A Grignard reagent prepared from 4-trifluoromethoxybromobenzene (54 g, 220 mmol) and dried Mg (5.4 g, 220 mmol) in 250 ml ether solvent was cooled down to -50° C., followed by gradually dropwise adding thereto ethylene oxide (29.3 g, 670 mmol), gradually heating the resulting reaction mixture up to room temperature, further stirring it for one hour at room temperature, adding the reaction solution to 6N HCl (300 ml), extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, distilling the residue under reduced pressure by means of a Vigoureaux tube, to isolate a colorless liquid, 2-(4-trifluoromethoxyphenyl)ethanol (14.5 g, 70.3 mmol) having a b.p. of 82° to 84° C. under 3.5 Torr, adding to this liquid, xylene (60 ml) and HBr aqueous solution (47%) (60 ml), refluxing the mixture for 9 hours, adding water to the reaction mixture, extracting the resulting product with toluene, washing the reaction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying the resulting organic layer over magnesium sulfate, distilling off the solvent, distilling the residue under reduced pressure using Vigoureux tube, to isolate a colorless liquid, 2-(4-trifluoromethoxyphenyl)bromoethane (12.0 g, 51.9 mmol) having a b.p. of 75° C. under 4 Torr. The yield of this product from 4-trifluoromethoxybromobenzene was 23.6%.