Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[SH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.O>OS(O)(=O)=O>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[S:11][CH2:1][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: C=C(CCC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCC(CSc1nc2ccccc2s1)C(=O)O
Reaction time: 2 h

Procedure:
20.9 g of 2-methyleneglutaric acid are dissolved at 50°, with stirring, in 150 ml of 75% H2SO4, and 24.2 g of 2-mercaptobenzthiazole are added slowly. The reaction is exothermic and the temperature rises to 60°. The reaction mixture is then stirred for 2 hours at 55°. The resulting brown solution is poured into 500 ml of water and stirred for 1 hour. 600 ml of water are then added, and the white precipitate is filtered off. Recrystallisation from aqueous methanol gives 4-(benzthiazol-2-ylthio)-butane-1,3-dicarboxylic acid, melting at 152°-154°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:49])[CH3:47])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with dimethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O3 [(M+H)+] 692.3129, observed 692.3129.
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46](=[O:48])[NH2:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[CH2:10][C:9]([OH:49])=[O:8])[CH:30]=3)=[CH:39][CH:38]=2)=[CH:45][CH:44]=1)(=[O:48])[NH2:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 81 %

Procedure:
According to the procedure described in Example 5(a), 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in MeOH/EtOAc to provide 35 mg(81%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid as a yellow solid, mp 194-6° C. 1H NMR (CD3OD): δ 8.35 (d, 2H, J=6.5 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.75 (d, 3H, J=8.4 Hz), 7.70-7.52 (m, 6H), 7.28 (t, 1H, J=2.0 Hz), 6.90 (t, 1H, J=2.8 Hz), 6.52 (dd, 1H, J=6.9, 16.8 Hz), 1.20 (s, 9H). IR (KBr): 3400, 2962, 1665, 1606, 1511, 1402 cm−1. HRFABMS: Calculated for C32H34N5O5 (M+H+): 568.2560. Found: 568.2575. Anal. Calculated for C32H33N5O5.0.7HOAc.0.5CHCl3: C, 60.83; H, 5.47; N, 10.46. Found: C, 60.93, H, 5.88; N, 10.19.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:19][C:20]1[N:21]=[C:22]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:27])[NH:23][C:24]=1[CH3:25]
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 60 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (20a) (0.22 g, 0.85 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.11 g, 0.64 mmol), WSC hydrochloride (0.63 g, 3.28 mmol) and DMAP (84 mg, 0.69 mmol), to obtain 0.15 g of the title compound as a pale yellow solid (60%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>O.ClCCl>[C:14]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CN(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a mechanically stirred solution of 83.66 g (94.3 mL, 0.939 mol) of 2-dimethylaminoethanol (distilled) and 95 g (131 mL) of triethylamine (Aldrich gold label) in 1L of dry dichloromethane maintained at 0° to -15° C. was added dropwise 100 g (98.3 mL, 0.939 mol) of isobutyryl chloride. The mixture was stirred 30 min at room temperature and treated with a solution of 100 g of sodium bicarbonate in water. The organic layer was washed with dilute sodium bicarbonate solution, dried with sodium sulfate and distilled to give 46.2 g of 2-dimethylaminoethyl isobutyrate, b.p. 59°-64° C. (8-10 mm). 1H-NMR (360 MHz, benzene-d6): 1.06 (d, J=6.6 Hz, 6 H, Me2CH), 2.05 (s, 6 H, CH3N), 2.33 (t, J=6 Hz, 2 H, CH2N), 2.39 (sept, J= 6.6 Hz, 1 H, Me2CH), 4.11 (t, J=6 Hz, 2 H, CH2O). Anal Calcd for C8H17NO2 : C 60.35, H 10.76, N 8.80; found: C 60.82, H 10.95, N 9.01.
Reaction SMILES: Cl.N[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+].[S-:18][S-].[Na+].[Na+]>O>[SH:18][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: [S-][S-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(S)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
5.0 g of 2-amino-6-methylbenzoic acid hydrochloride was converted to a diazonium salt with concentrated hydrochloric acid and 2.3 g of sodium nitrite. Then, this diazonium salt was gradually dropwise added to a previously prepared sodium disulfide solution (which was prepared from 8.7 g of sodium sulfide nonahydrate, 1.1 g of sulfur, 1.5 g of sodium hydroxide and 15 ml of water) at from 0° to 5° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction solution was poured into a large amount of water, and concentrated hydrochloric acid was added thereto. Then, the mixture was extracted with ethyl acetate. A sodium hydrogen carbonate aqueous solution was added to the ethyl acetate layer, and sodium hydrogencarbonate-soluble components were extracted. 5.8 g of sodium pyrosulfate was added to the aqueous solution, and the mixture was refluxed for 30 minutes to complete the reaction. Concentrated hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was dried, and then the solvent was distilled off under reduced pressure to obtain 3.6 g (yield: 65%) of 2-mercapto-6-methylbenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[C:12]([O:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: CC(=O)Oc1cccc2c1ccn2-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CC(=O)Oc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from acetic acid 1-(4-aminophenyl)-1H-indol-4-yl ester and 4-chloro-3-(trifluoromethyl)phenyl isocyanate in the same manner as in Step C of Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21]CC)=[O:20])[C:13](=[O:30])[C:12]2=[O:31])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13](=[O:30])[C:12]2=[O:31])=[CH:32][CH:33]=1)#[N:2]
Reactant: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C#N)cc2)C(=O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
In 70 ml of 6N hydrochloric acid was dissolved 7.0 g of ethyl 3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate, and the solution was stirred at 50° C. for 1.5 hours and then cooled to room temperature. The reaction solution was adjusted to pH 4.0 with a 15% aqueous sodium hydroxide solution and the crystals precipitated were collected by filtration to obtain 4.6 g of 3-[4-[3-(4-cyanophenoxy)-propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@@H:12]1[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:34][CH2:35][CH3:36]
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)N(C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid butyl ester was prepared from rac-{4-[(3S,4R)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using butyl chloroformate instead of 4-fluoro-phenyl chloroformate and was obtained as a light yellow foam. MS m/e: 504.2 [M]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11]CC1C=CC=CC=1)[CH:7]=[C:6]([CH3:19])[N:5]=2>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[N:3]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[CH:7]=[C:6]([CH3:19])[N:5]=2
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCc4ccccc4)cc(C)nc32)c(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(-n2c(C)nc3c(N)cc(C)nc32)c(C)c1
Reaction time: 20 h

Procedure:
Add palladium hydroxide (2.0 g) to a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine (1.50 g, 4.05 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 40 psi for 20 hr. Filter the reaction mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq. NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate. Purify by flash column chromatography (3% MeoH in CH2Cl2) to obtain the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(O)[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C.C(=O)(O)[O-].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([F:29])[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: FC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 3.0 g of 8-chloro-5-(4-chlorophenyl)-5H-indeno[1,2-d]pyrimidin-5-ol in 50 ml of methylene chloride was cooled to 0° C. under a nitrogen atmosphere. Approximately 2.7 g of diethylaminosulfur trifluoride were added and the reaction was stirred overnight. The mixture was poured into an iced solution of potassium bicarbonate and extracted with ethyl acetate. The organic extract was washed with a sodium bicarbonate solution and a sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Crystallization from ethyl acetate/isooctane provided 2.29 g of the desired title product, m.p. 236°-237° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[CH2:25](Br)[CH:26]=[CH2:27]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:27][CH:26]=[CH2:25])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: C=CCBr
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: C=CCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and allyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Si:14]([O:21][C:22](=[CH2:28])/[CH:23]=[CH:24]/[N:25]([CH3:27])[CH3:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Si:14]([O:21][C:22]1[CH2:28][CH2:9][C:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)([C:10]([F:11])([F:13])[F:12])[CH:24]([N:25]([CH3:27])[CH3:26])[CH:23]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C=C(c1ncccc1Cl)C(F)(F)F
Reactant: C=C(/C=C/N(C)C)O[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CN(C)C1C=C(O[Si](C)(C)C(C)(C)C)CCC1(c1ncccc1Cl)C(F)(F)F
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A solution of Example 26A (612 mg, 2.95 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (966 mg, 4.25 mmol) in toluene (2.5 mL) was heated on a microwave at 60° C. for 30 minutes, and then 70° C. for 30 minutes. Purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 30 mL/min) to provide the title compound (787 mg, 1.81 mmol, 61.4% yield) as a light yellow oil. MS (DCI/NH3) m/e 435 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.8 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (100 mg, 0.21 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (45 mg, 0.64 mmol, 3.00 equiv), piperidine (9 mg, 0.11 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 24 mg (24%) of the title compound as a white solid, LC-MS (ES, m/z): 524 [M+H]+. H-NMR (CDCl3, ppm): 8.397 (1H, s), 7.628˜7.427 (3H, m), 7.283˜7.231 (1H, m), 7.203˜7.124 (2H, m), 6.979˜6.866 (2H, m),6.722 (1H, s), 5.717 (2H, s), 4.973 (1H, s), 4.8˜3.1 (4H, m),2.581˜2.045 (5H, m),1.329˜1.228 (2H, m),0.893 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:11]([F:16])[F:15])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cccnc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100° C. for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.45 (m, 1H), 6.90 (m, 1H), 6.60 (t, 1H; J=75 Hz), 4.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([O:14]C(=O)C2C=CC=C(Cl)C=2)[CH:13]=1)=[O:6].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([OH:14])[CH:13]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OC(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-chlorobenzoyl chloride (32.81 g, 187.5 mmol, Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (9.24 g, 75 mmol, Aldrich), triethylamine (31.43 mL, 225 mmol, Aldrich) and tetrahydrofuran (150 mL) dropwise with magnetic stirring and cooling in an ice-water bath. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was then diluted with water (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). After stirring for another 30 minutes, precipitate was collected to give crude 3-chloro-benzoic acid 5-(3-chloro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 31.74 g). Crude 3-chloro-benzoic acid 5-(3-chloro-benzoylamino)-2-methyl-phenyl ester (11.42 g, 28.5 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL), methanol (140 mL) and aqueous 1N sodium hydroxide (28.5 mL, 28.5 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove most of the organic solvent. The resulting suspension was diluted with water (90 mL) and saturated aqueous sodium bicarbonate solution (10 mL). After standing for 30 minutes, precipitate was collected, washed with water and dried to give 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 6.06 g).
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([Br:15])[CH:2]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:16]1[CH:21]=[CH:20][C:19]([N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:6]2[CH:1]=[CH:2][C:3]([Br:15])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)CC1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Yield: 67 %

Procedure:
A mixture of 4,4′-dibromodiphenylamine (7.3 g. 22 mmol), cyclohexane-1,4-dione (2.5 g., 23.3 mole), para-toluenesulfonic acid (0.1 g.) and toluene (100 ml) was kept at reflux with a Dean-Stark phase separator containing 4A molecular sieves. After 18 hours at reflux, the reaction was diluted with toluene, and the toluene solution was washed with water, dried and concentrated. The residue was dissolved in hexanes, and the hexanes solution was passed through a column of silica gel to afford 4,4′-dibromotriphenylamine as a colorless glass, 5.04 g., 67% yield. Mass Spec (m/z): 401, 403, 405 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]C(O)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1C[O:34]CC1>>[C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nn1ccc2cc(CC(=O)O)ccc21
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)Nn1ccc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
To a −78° C. solution of 5-(carboxymethyl)-indole-1-carbamic acid tert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) was added DIBAL (127 mL of a 1 M solution in THF, 127 mmol), and the reaction mixture was stirred for 2.5 h. The reaction was quenched with 1:11 N HCl/MeOH (100 mL), the reaction mixture was warmed to room temperature, diluted with CH2Cl2 (100 mL), and separated. The organic solution was washed with saturated Rochelle salt, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) provided 5-hydroxymethylindole-1-carbamic acid tert-butyl ester as a yellow oil (6.5 g, 68%): 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J=9 Hz, 1H), 6.58 (d, J=6 Hz, 1H), 4.73 (s, 2H), 1.97 (s, 9H).