Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2([C:48](O)=[O:49])[CH2:47][CH2:46]2)=[O:44])=[CH:38][CH:37]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:39]5[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=5)[CH2:46][CH2:47]4)=[O:49])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 43 %

Procedure:
A crude product of [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (1.617 g) was dissolved in N,N-dimethylformamide (25 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.26 g), triethylamine (0.786 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.49 g) were added thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order and dried over anhydrous sodium sulfate. The solvent was removed to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1) to provide the titled compound as white powder (1.007 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2Cl)[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33](=[O:48])[C@@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH:36][CH2:35][C@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:48])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCCn1cnc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)ncnc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
1 g (3.72 mmol) of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester was dissolved in dimethylformamide (3 ml) and 2.6 ml (14.9 mmol) of N,N-diisopropylethylamine was added. 1.09 g (3.72 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and dimethylformamide (2 ml) were added. The reaction was stirred at 80° C. for 2 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with 10% aqueous citric acid solution and three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. Residual amounts of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester were removed as follows: the residue was dissolved in tetrahydrofuran and 2 g of a macroporous aminomethyl polystyrene resin was added. The suspension was heated at 60° C. for 5 hours, then stirred gently at room temperature for 16 hours. The resin was filtered off, washed with tetrahydrofuran, and the combined organic phase was dried in vacuo. Yield: 908 mg.
Reaction SMILES: C([Li])CCC.O1CCCC1.Br[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1.[S:22]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23]1>CCCCCC.O>[OH:28][CH:27]([C:24]1[CH:25]=[CH:26][S:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1
Reactant: O=Cc1ccsc1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccsc2)cc1OC
Temperature: 25 °C

Procedure:
24 ml of 2.5M n-butyl lithium in hexane are added dropwise to a tetrahydrofuran solution of 10.85 g 4-bromoveratrole under cooling. After stirring the mixture, 5.61 g of 3-thiophenecarboaldehyde are added thereto, and warmed to room temperature. Water is added thereto, and the mixture is extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove the solvent, whereby 3-(α-hydroxy-3,4-dimethoxybenzyl)thiophene is obtained. 2.8 g of sodium hydride are added to a solution of the product in dimethylformamide, and the mixture is stirred at room temperature. 4.7 ml of methyl iodide are added thereto, and the mixture is stirred. A small amount of water is added thereto, and the mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue and the mixture is extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by using silica gel column, whereby 10.5 g of 3-(α-methoxy-3,4-dimethoxybenzyl)thiophene are obtained.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C.[NH2:39][C@H:40]([C:44]([NH:46][CH:47]([CH:56]([OH:59])[CH2:57][F:58])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:45])[CH:41]([CH3:43])[CH3:42]>CN(C)C=O.C(Cl)Cl>[C:1]1([O:11][CH2:12][C:13]([NH:39][C@H:40]([C:44]([NH:46][CH:47]([CH:56]([OH:59])[CH2:57][F:58])[CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[O:45])[CH:41]([CH3:42])[CH3:43])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(O)COc1cccc2ccccc12
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a solution of (1-naphthyloxy)acetic acid (0.202 g, 1.0 mmol) in in dimethylformamide(4.0 mL)-CH2Cl2 (6.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.168 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.249 g, 1.3 mmol). After stirring for 10 min, the mixture was treated with a solution of (3RS,4RS)-3-(valinyl)amino-5-fluoro-4-hydroxypentanoic acid, tert-butyl ester (0.319 g, 1.04 mmol) in CH2Cl2(8.0 mL). After stirring at 0° C. for 1 hr and at room temperature for 3 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with EtOAc-hexane (3:2) to give the title compound (0.307 g, 63%) as a white solid. TLC(MeOH-CH2Cl2; 1:9) Rf=0.69.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.Br[C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C1C=CC(P([C:42]2[C:51]([C:52]3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=[C:50]3[C:45]([CH:46]=CC=C3)=[CH:44][CH:43]=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:51]([CH3:52])[C:50]=1[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH:10][C:15]3[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cc(C)c2nc(Nc3ccc(OCCN4CCCC4)cc3)nnc2c1
Reaction time: 24 h
Yield: 36.7 %

Procedure:
About 1 g (3.78 mmol) of 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine and about 2.04 g (7.56 mmol) of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine were dissolved in about 500 ml of toluene. About 174 mg (0.19 mmol) of Pd(dba)3, about 340 mg (0.54 mmol) of BINAP, and about 500 mg (4.46 mmol) KOt-Bu were added to the solution. The mixture was kept at about 100° C. for about 24 hours under argon. The crude product was purified by preparative HPLC. About 90 mg of [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (product having formula (IX)) was isolated. Yield: about 5.2%. ESI-MS: [M+H]+, 454.6; 1H NMR (DMSO-d6): δ 1.90-2.05 (m, 10 H), 2.64(s, 3 H), 3.15 (m, 2 H), 3.59-3.64 (m, 4 H), 4.31 (t, J=5.2 Hz, 2 H), 7.09(d, J=9.2 Hz, 2 H), 7.18 (d, J=7.4 Hz, 2 H), 7.23 (m, 1 H), 7.60 (s, 1 H), 7.91 (s, 1 H), 7.98 (d, J=9.2 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:36]=[C:37]=O)(=O)=O.ClS([NH-])(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[C:37]#[N:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3cc4cc(OCc5ccccc5)ccc4[nH]3)cc2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [NH-]S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a reaction flask 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole No. 141 (5.90 g, 14.6 mmol) was mixed with CH2Cl2 (90 mL) was cooled down to 0° C. (the starting material did not completely dissolve in CH2Cl2). While stirring vigorously, a solution of chlorosulfonyl isocyanate (2.26 g, 16.0 mmol) in CH2Cl2 (25 mL) was added dropwise over a period of 45 min. The reaction was run at 0° C. for 2 hrs while detected by TLC for the formation of the insoluble N-chlorosulfonylamide intermediate. After this period, Et3N (1.47 g, 14.6 mL) in CH2Cl2 (25 mL) was added dropwise over 45 min at 0° C. The insoluble residue became soluble in the reaction solvent as the Et3N addition was approaching completion. The reaction was let go for the additional 1 hr at 0° C. and 2 hrs at rt. The progress of the reaction could be observed by the insoluble solid formation of the product as the reaction time went on. The solvent was stripped down and the solid residue purified by trituration with methanol to yield (4.0 g, 63.8%). Mp=238-242° C.; 1H NMR (DMSO) 12.31 (s, 1H), 7.88 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.25 Hz), 7.55-7.30 (m, 7H), 7.23 (d, 2H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.2 Hz, 8.8 Hz), 5.20 (s, 2H), 5.17 (s, 2H); MS eI m/z 430 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (9.6 g, 16.1 mmol) in 4 M HCl in dioxane (60 mL), and water (15 mL) was heated at 100° C. for 20 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1 H), 8.22-8.14 (m, 2 H), 8.00-7.97 (m, 1 H), 7.72-7.65 (m, 3 H), 7.33 (d, J=7.2 Hz, 1 H), 3.04 (s, 3H); Mass spectrum m/z: 553.40 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N12CCN(CC1)CC2>C(Cl)Cl>[C:13](=[O:14])([O:8][CH:6]1[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)Oc2ccccc2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 23.2 grams (0.14 mole) of 95% 2,2,6,6-tetramethyl-4-piperidinol and 400 ml of methylene chloride. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 11.2 grams (0.07 mole) of phenyl chloroformate. The phenyl chloroformate was slowly added to the 2,2,6,6-tetramethyl-4-piperidinol solution without any appreciable exotherm. Then 0.5 grams of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 35° C. and a precipitate formed. Another 0.5 gram of DABCO was added but no further exotherm occurred. After stirring for 11/2 hours, the solids were filtered off and the methylene chloride solution was washed with water, 10% NaOH and water again, dried over anhydrous MgSO4, filtered and the solvent stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 17.4 grams (90% crude yield) which had a melting point of 62°-65° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1760 cm-1 and a moderate carbonyl peak at 1710 cm-1 .
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CCO.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:19]/[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
1M NaOH (4.8 ml) was added to a solution of 4-benzyloxybenzaldehyde (5 g) and cyclopropyl methyl ketone (3.96 g) in EtOH (24 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with H2O and EtOH. The mixture was stirred at ambient temperature for 20 minutes. Pale yellow crystals were collected and washed with H2O and 50% aqueous EtOH to give (2E)-3-[4-(benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.29 g).
Reaction SMILES: [C:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:13]=[CH:12][C:11]=2[C:10](I)=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CO.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>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:10]1[C:11]2[CH:12]=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:15][C:16]=2[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:9]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cnc(Oc3ccc(F)cc3F)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2cnc(Oc3ccc(F)cc3F)cc21
Yield: 66 %

Procedure:
A solution of 1-BOC-6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.071 g) and 2-chlorophenylboronic acid in 5 mL of benzene and 1 mL of methanol was stirred at room temperature for 15 minutes. To this solution was added tetrakis(triphenylphosphine)palladium catalyst (52 mg) and 0.3 mL of 1 M sodium carbonate. The resulting mixture was heated to reflux for five hours, cooled, filtered and the organic layer was separated. The organic layer was washed, dried and concentrated. The residue was purified via chromatography using 5% ethyl acetate in hexane as the eluent to afford 45 mg of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-pyrazolo[4,3-c]pyridine-1-carboxylic acid, tert-butyl ester (66% yield). Mass. Spec. M+H=458.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([N:28]5[CH2:29][CH2:30][N:25]([CH2:31][CH2:32][OH:33])[CH2:26][CH2:27]5)=[O:22])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N3CCN(CCO)CC3)ccc21
Yield: 67 %

Procedure:
[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazol-5-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (315 mg) was prepared by following General Procedure F starting 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (358 mg), 2-piperazin-1-yl-ethanol (143 mg), HBTU (419 mg), and DIEA (350 uL) in DMF (3 mL). LC/MS: m/z 470.6.
Reaction SMILES: [OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4].[OH-:34].[Na+]>>[OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]([NH2:12])=[O:34])[CH:3]([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.90 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.64 g of the title compound was obtained as a powder, melting at 153°-157° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]=[N:17][N:18]3[C:23]=2[C:22]2[CH:24]=[CH:25][NH:26][C:21]=2[N:20]=[CH:19]3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CO>[C:15]1([CH:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: OC1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Yield: 74.6 %

Procedure:
1-{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (500 mg, 1.35 mmol) in a mixture of dichloromethane (5 mL) and methanol (5 mL) was stirred with pyridinium p-toluenesulfonate (338 mg, 1.35 mmol) at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/1 (v/v)-ethyl acetate) to give the title compound as a colorless solid (259 mg, yield 75%).
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[C@H:18]2[C@@:13]([CH3:21])([C:14](=CC)[CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:22]=O.[Cl-].C[Al+]C.C([O:30][CH2:31][CH3:32])C>C1(C)C=CC=CC=1.CCCCCC>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@:13]2([CH3:21])[C@H:18]1[CH2:17][CH2:16][CH:15]=[C:14]2[C@H:32]([CH3:22])[CH2:31][OH:30])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC=C1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CCOCC
Reactant: C=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@H](CO)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a stirred solution of 3.11 g (10.1 mMol) of (1S,4aS,8aR)-tert-Butyl-(5-ethylidene-4a-methyl-decahydro-naphtalen-1-yloxy)-dimethylsilane in 125 ml of toluene are added 0.33 g (11.1 mMol) of finely powdered paraformaldehyde. The reaction mixture is cooled to 0° C. and 12.56 ml of a one molar solution of dimethylaluminumchloride in hexane are added and kept for one hour at this temperature. The reaction mixture is stirred at room temperature overnight, diluted with diethylether, washed with 1N HCl and with water, then dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed over a medium pressure 250 g silica gel column with hexane/ethylacetate 9/1 to yield 2.31 g (67.5%) of pure (S)-2-[(4aR,5S,8aS)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphtalen-1-yl]-propan-1-ol as an oil.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:4]=[CH:5][C:6]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:1][CH:2]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Yield: 125 %

Procedure:
Using the procedure described in Example 1, Part E, 1-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (970 mg, 3.1 mmol) was treated with 124 mg (3.1 mmol) of 60% NaH/mineral oil and then 0.29 mL (3.1 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 747 mg (63% yield) of [[1-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 164-167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:4]1[N:3]=[C:2]([S:11][CH3:10])[N:7]=[CH:6][CH:5]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1nccc(C#N)n1
Yield: 65.7 %

Procedure:
A mixture of 2-chloro-6-cyanopyrimidine (2.20 g, 15.8 mmol), sodium thiomethoxide (1.22 g, 17.3 mmol) and THF (100 ml) was refluxed for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.57 g, 66%) as pale yellow crystals.