Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[Br:3][C:4]1[C:5]([NH:11][C@H:12]([CH3:15])[CH:13]=[O:14])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1.[C:16](=O)=O.[Al].[Cl-].[NH4+]>C(OCC)C>[Br:3][C:4]1[C:5]([NH:11][C@H:12]([CH3:15])[C@H:13]([OH:14])[CH3:16])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1
Reactant: O=C=O
Reactant: C[C@H](C=O)Nc1nc(Cl)ncc1Br
Agent: [Al]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Product: C[C@@H](O)[C@@H](C)Nc1nc(Cl)ncc1Br
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
32.7 g (159 mmol) of copper(I)bromide dimethyl sulfide complex is introduced under nitrogen atmosphere into 1000 ml of diethyl ether and cooled to −78° C. Over a period of about 25 minutes, 200 ml of a 1.6 molar solution of methyllithium in diethyl ether is added in drops, and then the cooling bath is removed. The batch is stirred for 40 minutes, and the temperature increases to −35° C. It is cooled to −55° C., and 18.9 g (71.5 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propanal is added over a period of 20 minutes. It is stirred for 6 hours at −55° C., then the cooling bath is filled with dry ice again, covered with aluminum foil, and the batch is stirred overnight. 200 ml of a saturated ammonium chloride solution is added in drops, and the batch is heated to room temperature. It is diluted with 500 ml of diethyl ether, the organic phase is separated, and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with saturated ammonium chloride solution and saturated NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 4:1-1:1). 8.4 g (30.0 mmol, corresponding to 42% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2ccccc12
Yield: 52.7 %

Procedure:
Ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g) was dissolved in ethyl acetate (1000 ml) and 10% palladium-carbon (8.0 g) was added. The mixture was stirred with hydrogen (60 kg/cm2) at 55° C. for 5 hr. The reaction mixture was cooled and the catalyst was filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give ethyl 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (24.5 g).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:3]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1ccc(Cc2c(Br)[nH]c3ccccc23)cc1
Reactant: CCOC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a vigorously stirred solution of 0.32 g of the product from Step 2 in 5 mL of DMF was added sequentially 0.045 g NaH (60% in mineral oil), 0.2 mL of ethyl 4-bromobutyrate and 0.02 g of n-Bu4NI. The mixture was stirred for 45 minutes at room temperature, quenched with 5 mL of saturated aqueous solution of NH4Cl and 5 mL of water, and extracted with 40 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluted with 9:1 hexane/EtOAc to give 0.3 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][N:13]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:27][C:28](OC(C)=O)=[O:29]>>[C:28]([N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:12][N:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=2)[NH:9]1)(=[O:29])[CH3:27]
Reactant: Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1NC(c2ccc(N)cn2)=NN=C1c1ccccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A dry round-bottom flask was charged with 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,2,4,5-tetrazine (0.020 g, 0.08 mmol) and cooled to 0° C. Et3N (0.012 mL, 0.12 mmol) was added followed by Ac2O (0.6 mL), which was added dropwise via syringe. The reaction mixture was allowed to stir at room temperature for 3 h and then concentrated under reduced pressure. The crude residue was chromatographed on silica gel using a gradient (0-100%) of acetone in hexanes as the eluent to give 13 mg (0.04 mmol, 56%) of the title compound as a reddish pink solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:15]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
To 7-azaindole 1 in dichloromethane was added 6-chloronicotinoyl chloride 8, followed by aluminum chloride, under an atmosphere of nitrogen at −10° C. The reaction was stirred and allowed to warm to room temperature overnight. The reaction was quenched with 3 N hydrochloric acid and concentrated hydrochloric acid was added until all solids dissolved. The mixture was extracted with dichloromethane and the combined organic portions were dried with magnesium sulfate, filtered, and the filtrate was concentrated. The resulting solid material was recrystallized from chloroform/hexane to provide (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>CN(C=O)C.C(O)CCC.C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:27][C:26]([O:25][CH3:24])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(COc2ncnc3nc[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21
Reaction time: 0.25 h

Procedure:
6-Benzyloxypurine (4.18 g; 18.5 mmol) was added to a suspension of potassium carbonate (3.1 g; 22.4 mmol) in DMF (100 ml). After 15 min., bromoacetic acid methyl ester (1.93 ml; 20.4 mmol) was added. The reaction was monitored by TLC in butanol:acetic acid:water 4:1:1. Upon completion, the reaction mixture was partitioned between water (600 ml) and ethyl acetate (600 ml). The organic phase was dried over magnesium sulfate and evaporated to a volume of ˜10 ml and precipitated with pet. ether. The two products were separated by column chromatography using ethyl acetate as the solvent. The products were precipitated in pet. ether. Yield: 2.36 g (43%). Melting point: 111.5-115° C. UV λmax=250 nm (9-alkylated); λmax=260 nm (7-alkylated). 1H-NMR (DMSO-d6): 8.60 (1H, s); 8.43 (1H, s); 7.6-7.35 (5H, m); 5.69 (2H, s); 5.26 (2H, s); 3.75 (3H, s).
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].C([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[CH:20][CH:19]=1)(=O)C.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12]
Reactant: O=C1CCCCCCCCC(=O)O1
Reactant: CC(=O)Oc1ccc(OC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1cc(O)ccc1O
Reaction time: 72 h
Yield: 2.6 %

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added the previously made Oxacycloundecane-2,11-dione (37.95 g, 206 mmol), 1,4-diacetoxy-benzene (20 g, 103 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (68.7 g, 515 mmol) was added and the reaction stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collected by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 50 mL of 1 M aqueous sodium hydroxide and stirred for 1 hour. The solution was acidified with 1 M aqueous hydrochloric acid until pH=2. The crude product precipitate was collected by filtration and was re dissolved in acetonitrile (50 mL) and methylene chloride (15 mL) and allowed to precipitate slowly over a week. The resulting brown powder was collected by filtration and recrystallized from 10:3 acetic acid:water. The product (0.8 g, 3%) was isolated by filtration. Found: C, 65.55; H, 7.69%; C16H22O5 requires C, 65.29; H, 7.53%; 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 11.4, s, 1H (aryl-hydroxyl); δ 9.2, s, 1H (aryl-hydroxyl); δ 7.2 d, 1H (aryl H); δ 7.0, dd, 1H, (aryl H); δ 6.8, d, 1H (aryl H's), 3.0, t, 2H (CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.6, multiplet, 2H (CH2 β to carbonyl), δ 1.5, multiplet, 2H (CH2 β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]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][CH:12]=3)[C:3]=12.N1[CH2:40][CH2:39][CH2:38][CH2:37]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:37][CH:38]4[CH2:40][CH2:39]4)[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.26 mmol, 1.00 equiv), piperidine (27 mg, 0.28 mmol, 1.07 equiv) and cyclopropanecarbaldehyde (28 mg, 0.40 mmol, 1.51 equiv) in methanol (8 mL) was stirred in sealed tube at room temperature for 24 h. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 85.4 mg (64%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 506 (M+1). 1HNMR (300 MHz, CDCl3, ppm) 8.392 (1H, s), 7.676˜7.581 (2H, t), 7.445˜7.393 (2H, t), 7.202˜7.097 (5H, m), 6.601˜6.566 (1H, d, J=10.5), 5.737 (2H, s), 5.010˜4.912 (1H, m), 4.691˜3.185 (4H, m), 2.464˜2.035 (5H, m), 1.275˜0.876 (4H, m).
Reaction SMILES: C([C:8]1[N:9]=[C:10]([CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[NH:11][CH:12]=1)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>N>[NH:9]1[CH:8]=[CH:12][N:11]=[C:10]1[CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(OCC)C(Cc1nc(Cc2ccccc2)c[nH]1)P(=O)(OCC)OCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CCOP(=O)(OCC)C(Cc1ncc[nH]1)P(=O)(OCC)OCC

Procedure:
3.3 g (0.0072 mole) of tetraethyl 2-(benzylimidazol-2-yl)ethane-1,1-diphosphonate are dissolved in 50 ml of liquid ammonia and, with stirring, 1.0 g of sodium is added gradually in small portions until the blue colour of the solution is maintained for some time. Then 2.35 g of ammonium chloride are added in portions. The ammonia is then removed by evaporation, the residue is taken up in diethyl ether, the solution is filtered and the filtrate is concentrated by evaporation, affording tetraethyl 2-(imidazol-2-yl)ethane-1,1-diphosphonate as a colourless oil.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C(O)C>[ClH:1].[CH3:2][CH:3]([N:18]=[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC1=NCCCCC1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
A mixture of 15.0 g of α-methyl-p-phenethylbenzylamine hydrochloride and 25 ml of O-methylcaprolactim is stirred into a slurry and allowed to stand at room temperature for 4 days with occasional stirring. Small portions of absolute ethanol are added to keep the slurry stirrable. The mixture is then cooled to -20° C., the precipitate is collected, washed with small portions of absolute ether and recrystallized from a mixture of acetone-methanol to yield 15.7 g (76% yield) of the desired product, M.P. 230°-231° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8]2=[O:23])=[O:4].[OH-].[Na+]>CO>[O:23]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH2:10][N:9]1[CH2:14][CH2:15][NH:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2

Procedure:
A methanol solution (25 mL) of ester 6-3 (400 mg, 1.28 mmol) and 1 N NaOH (5 mL, 5 mmol) was stirred under ambient conditions for 18 hr. The reaction solution was concentrated to dryness and the residue was neutralized with 1 M NaHSO4 solution to provide 6-4 as a pale yellow solid.
Reaction SMILES: O1CCCCC1CC(=O)C.[CH3:11][C:12]1([CH2:25][O:26]C2CCCCO2)[CH2:21][C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[O:13]1.CC1(COC2CCCCO2)CC(O)C2[C:36](=[CH:37][CH:38]=[C:39]([C:45]#[N:46])C=2)[O:35]1.CC1(COC2CCCCO2)C=CC2C(=CC=C(C#N)C=2)O1.Cl>>[OH:26][CH2:25][C:12]1([CH3:11])[CH:21]=[C:20]([N:46]2[CH:45]=[CH:39][CH:38]=[CH:37][C:36]2=[O:35])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[O:13]1
Reactant: CC1(COC2CCCCO2)CC(O)c2cc(C#N)ccc2O1
Reactant: CC1(COC2CCCCO2)CC(=O)c2cc(C#N)ccc2O1
Agent: CC(=O)CC1CCCCO1
Agent: CC1(COC2CCCCO2)C=Cc2cc(C#N)ccc2O1
Agent: Cl
Product: CC1(CO)C=C(n2ccccc2=O)c2cc(C#N)ccc2O1

Procedure:
A mixture of 1 g of 2-methyl-2-(2-tetrahydropyranyloxymethyl)-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chroman [obtainable from 1-(2-tetrahydropyranyl)2-propanone via 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-4-chromanone, 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-4-chromanol, 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-3-chromene and the corresponding 3,4-epoxide] and 15 ml of 10% methanolic HCl solution is boiled for 15 min. Cooling and customary working up gives 2-hydroxymethyl-2-methyl-4-(1,2-dihydro2-oxo-1-pyridyl)-6-cyano-3-chromene. Example 5
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH3:12][C:13]([O-])(C)[CH3:14].[K+].C(Br)C=C>C1COCC1>[CH2:14]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[CH:13]=[CH2:12]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1ccc2cc(OC)ccc21
Reaction time: 1 h

Procedure:
5-Methoxyindole (294 mg, 2.0 mmol) was dissolved in THF (10 mL) and treated with 1M KOtBu in THF (2.2 mL, 2.2 mmol). After stirring for 1 hour, allyl bromide (190 μL, 2.2 mmol) was added and the reaction mixture was stirred for an additional 2 hrs. Standard aqueous workup provided N-Allyl-5-methoxyindole as an off white solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[K+].[CH:13](=[O:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([CH3:15])[CH:13]=[O:16]
Reactant: CCC=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C=O)=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
2,4-dichlorobenzaldehyde (26.26 g, 0.15 mol) was dissolved in toluene (200 mL), and then KOH (8.4 g, 1 eq) in water (183 mL) was added followed by BnEt3NCl. The mixture was cooled to 0° C. and n-propanal (26.15 g, 0.45 mol, 3 eq) in toluene (50 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The organic layer was separated and washed successively with water, brine, dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-1-2-3% EtOAc in hexanes) to give 17.56 g of 3-(2,4-dichlorophenyl)-2-methylpropenal.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])[N:10]=[CH:9]2)C=CC=CC=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[OH:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: OC[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@H]1C[C@H]1c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of N-triphenylmethyl-4-(trans-2-hydroxymethyl-cyclopropyl)imidazole (100 mg, 0.26 mmol) and trifluoroacetic acid (TFA) (10 mL) was stirred at room temperature for 1-3 hours. The TFA was evaporated under reduced pressure. The resulting mixture was diluted with distilled water (5 mL) and extracted with ether (3×15 mL). The aqueous layer was lyophilized to give the product (61 mg, 93% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:24]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1cn(C)nc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cn(C)nc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Yield: 83.4 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (171 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (229 mg, 83%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:24][CH:23]=1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Clc1ccc(CCBr)cc1
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(Cl)cc3)CC1)CC2
Yield: 63.7 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 4-chlorophenethyl bromide (240 mg) were treated as in Example 2 to give the title compound (240 mg) as white scaly crystals (yield: 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:27][NH:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([OH:40])=[CH:37][CH:38]=2)[N:33]([CH3:41])[C:32]=1[CH3:42])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:21]([O:20][C:19](=[O:25])[N:18]([C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:40][C:36]3[CH:35]=[C:34]4[C:39]([C:31]([C:29]([NH:28][CH3:27])=[O:30])=[C:32]([CH3:42])[N:33]4[CH3:41])=[CH:38][CH:37]=3)[CH:8]=2)=[O:12])[CH2:14]1)[CH3:26])([CH3:24])([CH3:23])[CH3:22]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](N(C)C(=O)OC(C)(C)C)C5)sc34)ccc12
Yield: 39.5 %

Procedure:
This material was prepared by the reaction of tert-butyl (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl(methyl)carbamate 34c (0.181 g, 0.46 mmole) with 6-hydroxy-N, 1,2-trimethyl-1H-indole-3-carboxamide 16e (0.10 g, 0.46 mmole) and Cs2CO3 (0.149 g, 0.46 mmole) in a manner as previously described for example 1 to give a yellow solid (0.105 g, 40%). 1H NMR (300 MHz, CDCl3) δ8.48 (1H, d, J=5.4 Hz), 7.82 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=2.1 Hz), 7.02 (1H, dd, J=2.1, 8.7 Hz), 6.56 (1H, d, J=5.4 Hz), 5.91 (1H, d, J=4.7 Hz), 4.82 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.68 (1H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.7 Hz), 2.84 (3H, s), 2.73 (3H, s), 2.17 (2H, m), 1.45 (9H, s); HRMS (MH+): Calcd: 578.2450. Found: 578.2437.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]nnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.10-8.20 (m, 1 H), 8.22-8.31 (m, 1 H), 8.49 (dt, J=8.1, 2.0, 1.7 Hz, 1 H), 8.75-8.92 (m, 2 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 265 (M+H)+.