Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH:20](C(OC(C)(C)C)=O)[N:14]3[C@H:13]3[CH2:28][CH2:29][N:30]=[CH:31][C@H:12]23)[CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:12]23)[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1CSc2cc(-c3cccc(Cl)c3Cl)cc3c2N1[C@H]1CCN=C[C@H]31
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCS3)c1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl(6bR,10aS)-5-(2,3-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole carboxylate (10 mg, 0.21 mmol) in CH2Cl2 (4.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 20° C. for 1 h then concentrated in vacuo. The residue was dissolved in H2O and the solution was adjusted to pH 2 by addition of 1N HCl. The aqueous layer was washed with Et2O then basified to pH 12 by addition of 50% NaOH. The solution was extracted with CHCl3, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (79 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ1.93-2.05 (br-s, 2H), 2.65-2.99 (m, 4H), 3.01-3.25 (m, 4H), 3.44-3.68 (m, 3H), 6.88 (s, 1H), 6.90 (s, 1H), 7.18 (d, J=4.6 Hz, 2H), 7.40 (t, J=4.6 Hz, 1H) ppm.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccc(Cl)cc2Cl)n1
Reaction time: 1.5 h

Procedure:
A suspension of 7.97 g. of 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred under nitrogen as 4.61 g. of ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 8.99 g. of 2,4-dichlorobenzyl chloride in 30 ml. of dry dimethylformamide is added during ca. 10 minutes. Stirring is continued for 5 hours and then 25 ml. of glacial acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred throughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution and filtered. The crude product is dissolved in 5 liters of boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 500 ml. and chilled. The crystalline solid is collected and again recrystallized from methanol to afford 6.33 g. of the title compound, m.p. 249°-250° C., NMR (dDMSO and D2O): δ 5.58 (singlet, N--CH2 --C6H3Cl2), 6.68 (doublet, J=8 Hz, 5H), 7.10 (doublet, J=3 Hz, 9H), 7.52 (doublet, J=3 Hz, 8H), 7.68 (doublet, J=8 Hz, 6H) p.p.m.; λmax95%EtOH 258 mμ (26,000) and 315 mμ (8,500).
Reaction SMILES: [NH2:1][C:2]1[C:10](Br)=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[CH:4][CH:3]=1.C[C:14]([N:16](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:1][C:2]1[C:10]([C:14]#[N:16])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1Br)C(O)CC2
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c(N)ccc2c1C(O)CC2
Temperature: 140 °C

Procedure:
A suspension of 6-amino-7-bromoindan-1-ol (1 g, 4.3 mmol), zinc cyanide (290 mg, 2.6 mmol), zinc (140 mg, 2.1 mmol), Pd(dba)3 (10 mol %), and dppf (50 mol %) in dimethylacetamide (8 ml) is heated at 140° C. under nitrogen for six hours. The solvent is distilled off at 100° C. under vacuum, the residue treated with dichloromethane, filtered through Celite, and the filtrate is washed with water. The organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Chromatographic purification by using ethyl acetate/hexane as eluent gives 6-amino-7-cyanoindan-1-ol as solid; LC/MS: 175 (M+1)+.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].N1C=CC=CC=1.O=S(Cl)Cl.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])=[O:38])=[CH:33][C:32]=1[C:45]1[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH:46]=1>C(Cl)Cl>[C:41]([NH:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])=[C:32]([C:45]2[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH:46]=2)[CH:33]=1)(=[O:39])=[O:38])([CH3:44])([CH3:42])[CH3:43]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2N)CC1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 363.2 %

Procedure:
A solution of 300 mg (0.976 mmol) of 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (as prepared in Example 48, step (a)) in toluene (8 mL) and EtOH (4 mL) was treated with 253 mg (1.07 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3.90 mL (7.81 mmol) of 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 113 mg (0.0976 mmol) of Pd(PPh3)4, and heated to 80° C. for 6 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1-4% MeOH—CH2Cl2 afforded 158 mg (48%) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide as a colorless glassy solid. A suspension of 215 mg (0.704 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) in CH2Cl2 (10 mL) was treated with 60.0 μL (0.704 mmol) of pyridine for 5 min. The mixture was then treated with 51.4 μL (0.704 mmol) of SOCl2 at RT for 30 min. A solution of 158 mg (0.0470 mmol) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide (as prepared earlier in this step) in CH2Cl2 (5 mL) was treated with the acid chloride solution and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 100.0 mg (17%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.95 (br s, 1H), 8.55 (d, 1H, J=8.8 Hz), 7.78 (dd, 1H, J=8.8, 2.4 Hz), 7.78 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 5.92 (s, 2H), 5.84-5.80 (m, 1H), 4.55 (br s, 1H), 3.68-3.62 (m, 2H), 2.32-2.24 (m, 2H), 2.14-2.08 (m, 2H), 1.63-1.56 (m, 2H), 1.23 (s, 9H), 1.11 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9](Cl)=[O:10].[CH3:13][C:14]1[CH:15]([OH:22])[CH2:16][C:17](=[CH2:21])[C:18]=1[CH2:19][CH3:20].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9]([O:22][CH:15]1[CH2:16][C:17](=[CH2:21])[C:18]([CH2:19][CH3:20])=[C:14]1[CH3:13])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=C1CC(O)C(C)=C1CC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C(C)=C1CC
Yield: 90 %

Procedure:
540 mg of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid chloride was added under ice-water cooling to a mixed solution of 400 mg of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol, 5 mg of 2,6-di-t-butyl-4-methylphenol and 274 mg of pyridine in 6 ml of toluene. The reaction was allowed to react at an ambient temperature for eight hours. The reaction solution was added to a 5% citric acid solution under ice-water cooling and extracted three times with diethyl ether. The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography to yield 751 mg of (RS)-2-methyl-4-methylidene-3-ethyl-2-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No.1). Yield 72% (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-t-butyl-4-methylphenol 0.1%)
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu]Cl.[Cu].N1C=CC=CC=1>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)c2ccccc12
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: [Cu]
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccccc2)c2ccccc12
Yield: 33 %

Procedure:
To a 3-neck flask fitted with a mechanical stirrer, 600 mL of pyridine (dried over molecular sieve), 100 g of 4-bromo-1-methylnaphthalene, 55.6 g of phenol, 83.7 g of potassium carbonate, 14.9 g of copper(I)chloride, and 2 g copper bronze was added. Under a nitrogen atmosphere, the mixture was refluxed for 72 hours with vigorous stirring. The reaction mixture was cooled and poured into cold dilute hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed two times with cold dilute hydrochloric acid, dried over sodium sulfate, and filtered. After removing the solvent under vacuum, the product was flash chromatographed over silica gel with hexane elution. The product was further purified through fractional distillation, obtaining 35 g (33%) of the desired 1-methyl-4-phenoxynaphthalene intermediate at 150° C. at 0.075 torr.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1.Cl.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:40]5[CH:39]=[CH:38][N:37]=[CH:36][CH:41]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 37.1 %

Procedure:
To sodium bicarbonate solution were added 4-(5-chlorobenzofuran-2-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (215 mg) and chloropyridine hydrochloride (144 mg), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (15 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=15:1) to give colorless solid of 4-(5-chlorobenzofuran-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (87 mg), which was treated with hydrochloric acid to give colorless solid of the title compound (80 mg) as hydrochloride salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B.CO>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: B
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 80.7 %

Procedure:
8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to −10±5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at −10° C. and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1([C:22](O)=[O:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1.O>C(O)C>[CH2:1]([O:3][C:6]([C:7]1([CH2:22][OH:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1)=[O:5])[CH3:2]
Reactant: COc1ccc(C(=O)N2CCC(CO)(C(=O)O)C2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(CO)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
Acetyl chloride (80.2 mL, 1130 mmol) was added to a suspension of 3-hydroxymethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid (210.0 g, 751.9 mmol) (see Preparation 9) in ethanol (2100 mL) and the reaction mixture was heated at 80° C. for 4 hours. Water (200 mL) was added then ethanol was removed by concentration under reduced pressure. The aqueous residue was partitioned between ethyl acetate (2 L) and saturated aqueous NaHCO3 (1500 mL). The organic layer was separated, washed with water (1500 mL) then concentrated under reduced pressure to afford the title compound as a colourless oil (140.7 g, 61%). (99.3:0.7 ratio of isomers)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[N:6][CH:7]=1.Br[C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:28][C:19]1[C:18]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1
Reactant: Cc1cc2c(cc1Br)OCCO2
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1cc2c(cc1-c1cnc(N)cn1)OCCO2
Temperature: 85 °C
Yield: 21.7 %

Procedure:
The 5-aminopyrazine-2-boronic acid pinacol ester (400 mg, 1.8 mmol) and 182 (550 mg, 2 mmol) was dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. The 4 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 2 min before bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 70 mg, 0.1 mmol) was added. The reaction was heated at 85° C. for 2 h. The reaction mixture was worked-up with EtOAc extraction. The product was purified by flash column and afforded 184 (95 mg, 20%) as yellow wax. LC-MS: calcd. for C13H13N3O2: 244 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([OH:7])=O.FC(F)(F)C(O)=O.[CH:34]1[S:35][CH:36]=[C:37]2[CH2:41][NH:40][CH2:39][C:38]=12.C(N(CC)CC)C>ClCCl.CN(C)C=O.O>[O:7]=[C:5]([N:40]1[CH2:39][C:38]2=[CH:34][S:35][CH:36]=[C:37]2[CH2:41]1)[CH2:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: c1scc2c1CNC2
Reactant: O=C(O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
0.49 ml (6.8 mmol) of thionyl chloride is added, at 0° C., to a solution of 1.01 g (3.4 mmol) of phenylmethyl 3-carboxy-2-(phenylmethyl)-1-propanoate in 15 ml of dichloromethane, followed by two drops of N,N-dimethylformamide. After 2 h at room temperature, the mixture is evaporated to dryness and the residue is dissolved in 25 ml of dichloromethane. The solution is cooled to 0° C. and then a solution of 0.81 g (3.4 mmol) of 5,6-dihydro-4H-thieno[3,4-c]pyrrole trifluoroacetate and 1.42 ml (10.2 mmol) of triethylamine in 25 ml of dichloromethane is added. After 16 h at room temperature, 25 ml of water are added, and the organic phase is decanted off, washed with a saturated sodium chloride solution and then dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on a silica gel with the aid of the eluent mixture ethyl acetate/hexane 3/7. 0.52 g of a white solid is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[C:7]([C:17]#[C:18][Si](C)(C)C)[N:6]=1)=[O:4].CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1>[NH2:11][C:10]1[N:9]=[C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[CH:18]=[CH:17][C:7]2=[N:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COCCNc1nc(N)c(C(=O)OC)nc1C#C[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCn1ccc2nc(C(=O)O)c(N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-(2-methoxy-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylic acid methyl ester (487 mg, 1.51 mmol) in THF (7.6 ml) was added a suspension of KOtBu (356 mg, 3.17 mmol) in THF (7.6 ml) and the reaction mixture was stirred at r.t. for 2 h. At 0° C. solid NH4Cl (848 mg) was added and the mixture stirred for 30 min. After addition of half-saturated NH4Cl solution (15 ml) the mixture was extracted with EtOAc (2×15 ml), the pH of the aq. phase was adjusted the pH to 4 by addition of 1N HCl. The aq. phase was extracted with DCM/EtOH 9:1 (2×100 ml), the combined organic layers were dried with Na2SO4 and evaporated. The residue was filtered through a plug of silica gel (DCM/EtOH 90:10) to provide the title compound as brown powder. This material was used for coupling reactions without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:19][C:18]([C:33]([C:39]([F:42])([F:41])[F:40])([C:35]([F:38])([F:37])[F:36])[OH:34])=[N:17]1.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].ClCCl>O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH2:28][CH2:29][N:30]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:19][C:18]([C:33]([C:39]([F:40])([F:41])[F:42])([C:35]([F:36])([F:37])[F:38])[OH:34])=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(C3=CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole trifluoroacetate (30.0 mg, 0.05 mmol) prepared in Example 399, triethylamine (20.3 uL, 0.15 mmol) and methanesulfonyl chloride (4.6 uL, 0.06 mmol) were added at 0° C. to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 12 hours and then distilled water was added thereto. The reaction mixture was extracted with dichloromethane two times. The combined extract was washed with a 1N hydrochloric acid solution, a saturated solution of sodium carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 2.1 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[CH:19]4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:35][CH:36]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Reactant: COC(=O)Cc1ccc(CBr)cc1
Product: COC(=O)Cc1ccc(COc2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenol (Example 147, step 5) was reacted with (4-bromomethyl-phenyl)-acetic acid methyl ester to give {4-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenoxymethyl]-phenyl}-acetic acid methyl ester. This compound was hydrolyzed in analogy to Example 141 to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=528.0 [M-−H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Cl>CO.O>[OH:17][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol (0.033 g, 0.3 mmol) in MeOH:H2O (1.8:0.2 mL; v/v) was shaken in a sealed tube at 100° C. for 24 h (or 80° C. for 3 days), cooled to room temperature, diluted with water (15 mL), acidified with 2N HCl (pH>2). Upon saturation with sodium chloride it was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate and solvent was removed. The resulting residue was filtered through a pad of silica gel (200–400 mesh) using CH2Cl2->1>10% MeOH in CH2Cl2 to obtain the desired N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218). If the reaction scale is large enough, solid of the resulting product can be isolated by filtration. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=5.1 Hz), 7.12–6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd, 1H, J=1.2 and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS (m/e): 313 (MH+).