Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[C:18]([F:34])[CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[C:18]([F:34])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)c(F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A solution of 228 mg (1.03 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 10 min. to a solution of 286 mg (1.03 mmol) 3-[4-(4-amino-2-fluoro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by chromatography on silica (dichloromethane/ethanol 97:3). The obtained material was stirred with dichloromethane. The precipitate was filtered and dried to yield 130 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[S:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:15][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:9])[CH3:11]
Reactant: CCOC(CN)OCC
Reactant: S=C=Nc1ccccn1
Solvent: CCO
Product: CCOC(CNC(=S)Nc1ccccn1)OCC
Yield: 68.2 %

Procedure:
To a solution of 11.1 g of 2-pyridylisothiocyanate dissolved in 100 ml of ethanol, was added 10.0 g of aminoacetaldehyde diethylacetal, followed by stirring of the resulting mixture under reflux with heating for 40 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. Crystals precipitated were collected by filtration to give 13.8 g of N-2,2-diethoxyethyl-N'-(2-pyridyl)thiourea (m.p.: 132° to 133° C.). To the thus obtained crystals was added 120 ml of 10% diluted hydrochloric acid, followed by stirring of the resulting mixture under reflux with heating for 30 minutes. The reaction mixture was cooled and adjusted to pH of 5 to 6 with use of 50% aqueous sodium hydroxide to precipitate crystals. The crystals precipitated were filtered out, washed with water and dried to give 8.3 g of the desired compound. m.p.: 162° to 163° C.
Reaction SMILES: [Br:1]N1C(=O)C(C)(C)N(Br)C1=O.[C:12]([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][CH2:20][C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17]1)(=[O:14])[CH3:13]>>[C:12]([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][C@@H:20]([Br:1])[C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Yield: 43.5 %

Procedure:
16.3 g of dibromodimethylhydantoin were added to a solution of 42.8 g of cholesterol acetate in 300 ml of petroleum ether (40°-60° C.). The reaction mixture was refluxed for 1 hour while stirring thoroughly. After cooling, the solid (dimethylhydantoin) was filtered off; the solvent was distilled off from the filtrate under reduced pressure. In order to remove the last traces of solvent, 100 ml of acetone were added, after which the solution was again evaporated under reduced pressure. The residue was recrystallized from 50 ml of acetone; the α-epimer crystallized out at 0° C. After three recrystallizations from acetone, 12.6 g of pure 7α-bromocholesterol acetate were obtained having a melting-point of 113.9°-115.6° C.; according to the bromine content and the NMR spectrum, the substance was 100% pure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][C:25]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NC1(C(=O)O)CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopropanecarboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90-1.00 (m, 2H); 1.10-1.20 (m, 2H); 3.93 (s, 2H); 3.96 (s, 3H); 7.14 (s, 1H); 7.28 (m, 1H); 7.40-7.55 (m, 2H); 8.29 (s, 1H); 8.40 (s, 1H); Mass Spectrum: (M+H)+ 417. 1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid reacted with para-formaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.08 (m, 2H); 1.21 (m, 2H); 2.43 (s, 3H); 3.94 (s, 3H); 4.08 (s, 2H); 7.17 (s, 1H); 7.28 (t, 1H); 7.52 (m, 2H); 8.21 (s, 1H); 8.42 (s, 1H); 9.73 (s, 1H); Mass Spectrum: (M+H)+ 431
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[H][H]>CCO.[Pd]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1c2cccc(N3CCNCC3)c2ccn1Cc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: O=C1c2cccc(N3CCNCC3)c2CCN1Cc1ccccc1
Yield: 15.6 %

Procedure:
2-Benzyl-5-piperazin-1-yl-2H-isoquinolin-1-one (0.05 g, 0.16 mmol) from step 5 was added to a small (100 mL) Parr bottle, dissolved in 10 mL of EtOH, and a catalytic amount (25 mg) of palladium (10%) on charcoal was added (under N2 atmosphere). The vessel was then exposed to 60 psig hydrogen for 24 hours. Preparative HPLC gave the desired product, 2-benzyl-5-piperazin-1-yl-3,4-dihydro-2H-isoquinolin-1-one (8 mg, 0.025 mmol); M+H=322.
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12][CH:11]=1)=[O:8])=[O:5])C.[NH2:32][C:33]1[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1(C)C(C)=CC=CC=1>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([C:40]([F:42])([F:43])[F:41])=[CH:34][C:33]=1[NH:32][C:4]([CH2:6][C:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)=[O:8])=[O:5]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)OCC)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A solution of the product from (c) (47 g, 0.112 mol) and 3-amino-4-chlorobenzotrifluoride (21.9 g, 0.112 mol) in xylene (450 ml) were heated to reflux for 5 h. Over the final hour, the volume of the mixture was reduced to 200 ml by distillation. After cooling to about 80° C., the solution was poured into petrol (b.p. 60°-80° C. (1 liter) with rapid stirring. A pale yellow solid was collected by filtration and then recrystallized from petrol (b.p. 60°-80° C.) to give an off white solid (40.5 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.S(Cl)([Cl:23])=O>ClCCl>[Cl:23][CH2:12][C:4]1[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)cc2c1OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(CCl)c2c(c1)OCCO2

Procedure:
A solution of (7-fluoro-2,3-dihydro-1,4-benzodioxine-5-yl)methanol (436 mg, 2.36 mmol) and triethylamine (400 μL, 2.83 mmol) in dichloromethane (20 mL) was cooled to 0° C. and then slowly added thionyl chloride (260 μL, 3.55 mmol) and stirred for 45 min. The reaction mixture was partitioned with water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with aqueous saturated sodium bicarbonate, brine, and then dried over anhydrous magnesium sulfate and concentrated to give crude 5-(chloromethyl)-7-fluoro-2,3-dihydro-1,4-benzodioxine as a colorless oil. The crude residue was taken up in N,N-dimethylformamide (10 mL) and was added potassium cyanide (460 mg, 7.08 mmol). The reaction mixture was heated to 60° C. and stirred for 5 h, at which time it was cooled to room temperature and partitioned with water (100 mL) and ethyl acetate (150 mL). The organic layer was washed with 10% citric acid (3×100 mL) and then aqueous saturated sodium bicarbonate (2×100 mL). The organic solution was further washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 430 mg (94% over 2 steps) of (7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)acetonitrile as an off-white powder. GCMS for C10H8FNO2: 193 (M+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1C.Cl>ClC(Cl)C>[Br:16][C:17]1[S:18][C:19]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:20][CH:21]=1
Reactant: Cc1ccsc1Br
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)c1ccc(Br)s1
Reaction time: 4 h

Procedure:
1.90 g of phthalic anhydride and 3.58 g of aluminum chloride were dissolved in 40 ml of dichloroethane, and 2-bromo-3-methylthiophene was added dropwise to the solution at room temperature. After stirring the solution for 4 hours, the reaction solution was poured into a 1-N hydrochloric acid under cooling with ice, and extracted with chloroform. By purifying the extract by silica gel chromatography (eluent: chloroform, ethyl acetate), 1.70 g of o-(5-bromo-2-thenoyl)benzoic acid was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethylphenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35 g, 2.22 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.59 g, 73%). MS (ISP) 404.0 [(M+H)+]; mp 147° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:8]([Cl:17])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1>[Cl:17][C:8]1[C:9]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(OCC2CCC2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC2CCC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid methyl ester (339 mg, 1.33 mmol) in THF (10 mL) was added sodium hydroxide solution (2.65 mL, 1 N). The resulting solution was stirred at room temperature for 2 hours, and afterwards acidified with hydrochloric acid (10 mL, 1N) and poured into ethyl acetate (50 mL). The phases were separated and the water phase was extracted with additional ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material (286 mg, 89%) a white solid, was sufficiently pure to be used in the next step without further purification. MS (ESI, m/z): 240.1 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:22]=1)[C:7](=[O:21])[N:8](O)[C:9]3=[O:19].C1C(=O)N([Cl:30])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[C:6]2[C:5]3=[C:10]([CH:11]=[C:12]([Cl:30])[C:13]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:4]3[CH:3]=1)[C:9](=[O:19])[NH:8][C:7]2=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)c2cc(Cl)c(N3CCCC3)c3cc(Br)cc1c23
Yield: 45.2 %

Procedure:
A mixture of 5-bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.42 mmol, from Example 59) and NCS (0.072 g, 0.54 mmol) in acetic acid (12 mL) was reacted at 100° C. for 3 hours. The reaction mixture was cooled and poured into water. The resulting precipitate was collected by filtration, washed with water, and dried to give 0.072 g of the title compound.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12].[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[K+]>ClCCl>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=[N+]([O-])O
Reactant: FC(F)Oc1ccccc1OC(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC(F)F)c(OC(F)F)c1

Procedure:
A solution of 15 g of 1,2-bis(difluoromethoxy)-benzene and 15 ml of 100% strength nitric acid in 150 ml of dichloromethane is stirred at room temperature for 7 hours. The mixture is neutralized with potassium bicarbonate solution and the organic layer is separated off and chromatographed on silica gel by means of cyclohexane/ethyl acetate (4:1). 1,2-Bis-(Difluoromethoxy)-4-nitro-benzene is obtained. This is hydrogenated and acetylated analogously to Example 21a to give N-[3,4-bis(difluoromethoxy)-phenyl]acetamide (m.p. 81°-83° C.). Analogously to Example 21, furthermore, N-[4,5-bis(difluoromethoxy)-2-nitrophenyl]acetamide (m.p. 65°-67° C.), N-[4,5-bis(difluoromethoxy)-2-nitro]aniline (m.p. 107°-109° C.), 4,5-bis(difluoromethoxy)-1,2-phenylenediamine dihydrochloride and the title compound of m.p. 285°-287° C. (decomposition; from isopropanol) are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=[O:27])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:27])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CON(C)C(=O)C1CCCN1C(=O)OC(C)(C)C
Reactant: c1ccc2occc2c1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)c1cc2ccccc2o1

Procedure:
The title compound (2.7 g) was prepared from benzofuran (2.29 g) and (RS)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, D79 (5.00 g) according to a procedure similar to that for Description 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([N:15]4[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][CH:17]=[N:16]4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[CH:20]([C:19]1[N:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)[N:16]=[CH:17][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(-c3cn[nH]c3)cc1-2

Procedure:
Following the procedure for 484, Step 4, 9-bromo-2-(5-isopropyl-[1,2,4]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to afford 489 as a white solid. LCMS (Method C): RT=10.17 min, [M+H]+=379. 1H NMR (DMSO-d6): 12.95 (1H, bs), 8.42 (1H, d, J=2.3 Hz), 8.18 (1H, s), 8.07 (1H, bs), 7.81 (1H, bs), 7.51 (1H, dd, J=8.3, 2.3 Hz), 7.06 (1H, d, J=8.3 Hz), 4.36 (2H, t, J=5.0 Hz), 4.12-4.04 (1H, m), 3.38 (2H, t, J=5.0 Hz), 1.47 (3H, s), 1.46 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:3]=1
Reactant: Ic1n[nH]c2ncccc12
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(I)c2cccnc21
Yield: 83.1 %

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-b]pyridine (9.8 g, 40 mmol, 1 equiv) and potassium carbonate (27.6 g, 5 equiv) in 15 mL of DMF at 90° C. was added ethyl chloroacetate (8.5 mL, 40 mmol, 1 equiv). Two hours later, the reaction mixture was diluted with ethyl acetate followed by washing with saturated aqueous NaHCO3. The organic layer was dried and concentrated to provide the crude product. Purification of the crude product by flash chromatography gave ethyl (3-Iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetate (11 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.[OH-].[K+].CO.Cl>O>[F:20][C:2]([F:1])([F:21])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1O
Temperature: 0 °C
Yield: 39.5 %

Procedure:
A mixture of 13 g (0.041 mol) of product of Example 35, 10 g of KOH, 100 ml of methanol, 100 ml of water was held at reflux for 20 hours, cooled, and poured into ice water (500 ml) containing 20 ml of concentrated HCl. The mixture was extracted with ether. The ether solution was dried and concentrated to give a solid which was recrystallized from hexane to give 4.68 g (39%) of product; mp 161°-162° C. A second crop, 4.74 g (40%), mp 155°-159° C., was obtained from mother liquor. Total yield was 79%.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[N:7]=1.O>C1C=CC=CC=1.O.OO.[Ni]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[N:7]=1
Reactant: c1cc(C2=NCCS2)nc(C2OCCO2)c1
Agent: [Ni]
Agent: OO
Solvent: c1ccccc1
Solvent: O
Product: c1cc(-c2nccs2)nc(C2OCCO2)c1
Yield: 31.5 %

Procedure:
10 g of nickel peroxide hydrate are added in 1 g portions over 20 hours to a solution of 1.33 g of 2-(4,5-dihydrothiazol-2-yl)-6-[1,3]dioxolan-2-yl-pyridine (5.62 mmol) in 50 ml of benzene maintained under reflux with removal of the water formed continuously. The insoluble matter is removed by filtration on celite and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform/ethyl acetate; 85:15). 0.42 g of a white solid is recovered.
Reaction SMILES: [OH2:1].[ClH:2].[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.OO>C(O)(=O)C>[OH2:13].[ClH:2].[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:23])[CH2:18][CH2:19][S:20](=[O:1])[CH3:21])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1.[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:23])[CH2:18][CH2:19][S:20](=[O:1])[CH3:21])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1.[ClH:2]
Reactant: CN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCSC)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCS(C)=O)C(=O)NCCCc1ccccc1
Yield: 119.6 %

Procedure:
A solution of N-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride hydrate (4:1) (690 mg.) and aqueous hydrogen peroxide (3%, 1.95 ml.) in acetic acid (10 ml.) was stirred at room temperature, then stripped of volatiles. The residue was purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel (350 g.) using ammonium acetate (0.2%) in methanol-water (1:1) as the eluant. A solution of the product, which appeared in fractions 4-5 (centered at k'=2.0), in methanol (20 ml.) and hydrochloric acid (0.01 N, 100 ml.) was concentrated (to 60 ml.), filtered and lyophilized, affording as an amorphous solid N-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide S-oxide monohydrochloride hemihydrate (558 mg.; [α]D25 +59.8°, c=1, methanol), whose free base is the compound of Formula II wherein Q is Met(O), R1 is methyl, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=1[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:33](=[O:34])[CH2:32][C:25]2[CH:26]=[C:27]([F:31])[CH:28]=[C:29]([F:30])[C:24]=2[F:23])[CH2:4][CH2:5]3)=[CH:13]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (2,3,5-trifluorophenyl)acetic acid, HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS (62-A1-ON) indicated partial conversion, with a mixture of starting material, desired product and bis-acylated material, so the reaction mixture was poured into water (10 mL), and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water (10 mL), and dried at the pump for an hour. The beige solid was adsorbed onto silica, and purified by flash chromatography (0-10% methanol in DCM, 12-g column) to afford a pale yellow solid which showed presence of bis-acylated material. The product was adsorbed onto silica and purified by flash chromatography (100% EtOAc-10% MeOH in EtOAc, then 10% MeOH in DCM, 12-g column) to afford 7-methyl-5-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102 mg, 52.6% yield) as a white solid. LC-MS (ES) m/z=438 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): δ 3.28 (t, J=8.3 Hz, 2H), 3.74 (s, 3H), 4.04 (s, 2H), 4.29 (t, J=8.5 Hz, 2H), 6.08 (br. s., 2H), 7.10-7.17 (m, 1H), 7.20-7.28 (m, 2H), 7.34 (s, 1H), 7.42-7.53 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 8.15 (s, 1H).