Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:15])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([OH:16])[N:3]=1.S(=O)(=O)(O)N.N[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>>[Br:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([OH:16])[N:3]=[C:2]2[NH:1][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1
Reactant: CN1CCN(CCCN)CC1
Reactant: Nc1nc(O)nc2c(Br)cc([N+](=O)[O-])cc12
Agent: NS(=O)(=O)O
Product: CN1CCN(CCCNc2nc(O)nc3c(Br)cc([N+](=O)[O-])cc23)CC1
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 4-amino-8-bromo-6-nitro-quinazolin-2-ol (24.1 mg, 0.0845 mmol), sulfamic acid (16.4 mg, 0.169 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (1 ml) was heated at reflux for 7 h. The cooled reaction mixture was poured into 10 ml ice water. The resulting precipitate was collected and purified by preparative HPLC. 19.2 mg product was obtained. Yield: 40%; 1H NMR (500 MHz, DMSO-d6): δ 1.91521–1.95482 (m, 2H), 2.78103(s, 8H), 3.16555(b, 4H), 8.68221–8.68666(d, J=2.225 Hz, 1H), 9.10824–9.11291(d, J=2.335 Hz, 1H); ESI-MS: 425, 427 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
After a mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1150 mg), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1010 mg, yield: 93%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 178–179° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:5])=[O:4].[CH2:25](I)[CH3:26].O>CN(C=O)C>[CH2:25]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:21]([S:23][CH3:24])=[CH:22][C:6]=1[N+:3]([O-:5])=[O:4])[CH3:26]
Reactant: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(SC)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a suspension of sodium hydride (65%, 0.21 g (5.76 mmol)) in 4.0 ml of DMF, 2′-nitro-4′-methylthio-p-toluenesulfonanilide (1.50 g (4.43 mmol)) was added with stirring at room temperature. To the resulting mixture, after 30 minutes' stirring at room temperature, ethyl iodide (0.52 ml (6.21 mmol)) was added dropwise and the mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, dilute hydrochloric acid, and saturated aqueous solution of sodium chloride successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography with chloroform as eluent to give 1.04 g (64%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(Cl)Cl>[C:4]1([N:7]=[C:8]2[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][O:18]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: OCC1CCCCN1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(N=C2OCC3CCCCN23)cc1
Reaction time: 12 h

Procedure:
3 g Phenyl isocyanide dichloride in 10 ml methylene chloride was treated at room temperature with a solution of 5.4 ml triethylamine and 1.7 g 2-hydroxymethylpiperidine in 20 ml methylene chloride. After 12 hours at room temperature, the mixture was washed with water, the organic phase was dried over magnesium sulphate, the solvent was distilled and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]=[C:33]([N:35]3[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][CH2:41][N:35]([C:33]3[S:34][C:30]4[CH:29]=[C:28]([Cl:27])[CH:43]=[CH:42][C:31]=4[N:32]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc2nc(N3CCCNCC3)sc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccc(Cl)cc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]C)[N:9]=[C:8]1[N:16]=[C:17]([C:21]([O:23]CC)=[O:22])[NH:18][C:19](=[O:20])[C:7]1=[CH:6]2.COC1C=C(C([N+]([O-])=O)=CC=1OCC)C=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:16]=[C:17]([C:21]([OH:23])=[O:22])[NH:18][C:19](=[O:20])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OCC)c(OC)cc3cc2c(=O)[nH]1
Agent: CCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Product: COc1cc2cc3c(=O)[nH]c(C(=O)O)nc3nc2cc1OC

Procedure:
Ethyl 7-methoxy-8-ethoxypyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate is similarly prepared according to procedures A-C, beginning with 3-methoxy-4-ethoxy-6-nitrobenzaldehyde. It melts at 264°-265°C. (dec.)
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[NH:8]3)=[CH:4][C:3]=2[O:2]1.ClS([N:18]=[C:19]=[O:20])(=O)=O>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[N:8]3[C:19]([NH2:18])=[O:20])=[CH:4][C:3]=2[O:2]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2cc3c(cc2N1)OCO3
Product: NC(=O)N1C(=O)Cc2cc3c(cc21)OCO3

Procedure:
5,6-Methylenedioxy-2-oxindole-1-carboxamide was prepared by reaction of 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis, using the procedure of Example 19. The product melted at 237°-238° C. (dec.) after recrystallization from acetic acid.
Reaction SMILES: O.O.[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([O-:17])(=O)=[O:15])[CH:10]=2)[NH:5]1.[Na+].O=P(Cl)(Cl)[Cl:21].S1(CCCC1)(=O)=O>O>[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([Cl:21])(=[O:17])=[O:15])[CH:10]=2)[NH:5]1
Reactant: O=C1Nc2ccc(S(=O)(=O)[O-])cc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
A suspension of sodium 2,3-dioxoindoline-5-sulfonate dihydrate (5.0 g, 17.53 mmol) and POCl3 (8.17 ml, 88 mmol) in sulfolane (25 ml, 264 mmol) was heated at 60° C. for 3 hours. The solution was cooled to 0° C. and water (60 ml) was added drop wise; the green precipitate was filtered and washed with a small amount of water. The solid was dissolved in ethyl acetate and washed three times with water; the organic phase was then dried over sodium sulfate and evaporated to give a crude solid that was purified by crystallization from hexane/ethyl acetate 1:1 to give 2,3-dioxoindoline-5-sulfonyl chloride (3.52 g, 14.33 mmol, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19](OC)=[O:20])[CH2:14][CH2:13]2)[CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:9]2[CH2:10][CH2:11]2)[C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]2)=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)N(C1CC1)[C@H]1CC[C@H](CCO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(4-chloro-N-cyclopropylbenzamido)cyclohexyl)acetate (0.182 g, 0.52 mmol) in THF (3 mL) was added lithium borohydride (2 M solution in THF, 3.5 ml) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 5% MeOH—CH2Cl2. The desired alcohol product was obtained as a white solid (0.115 g). MS: 322 (M+1), C18H24ClNO2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.N1C(=O)C2NC=NC=2N[C:14]1=O>>[N:8]1([C:9](=[O:11])[C:10]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[NH:6][C:7]1=[O:12])[CH3:14]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Product: Cn1c(=O)[nH]c2ncn(C)c2c1=O

Procedure:
N-Demethylation of paraxanthine by Ndm also resulted in production of formaldehyde. After 90 minutes of incubation, 338.5±7.7 μM of paraxanthine was N-demethylated by 7.4 units of Ndm and approximately 540.6±20.9 μM of formaldehyde was produced (FIG. 5). 7-Methylxanthine (126.9±6.40 μM) and xanthine (193.7±4.0 μM) were the N-demethylated products. Tallying up all the products formed from paraxanthine, it was determined that approximately one molecule of formaldehyde was produced per methyl group removed.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=O)=[CH:27][CH:26]=1.C[O-].[Na+]>O1CCCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=[CH:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[C:3]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:4]=2)=[CH:37][CH:38]=1
Reactant: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A stirred solution of diethyl (4-fluoro-3-phenoxybenzyl)phosphonate (2.64 g, 7.8 mmol) and p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (1.35 g, 6 mmol) in tetrahydrofuran (20 mL) is treated with sodium methoxide (562 mg, 9.36 mmol) at 0° C., stirred at room temperature overnight, quenched with 2 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic extract is washed sequentially with water, 2 N aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel eluting with 1:9 ethyl acetate/hexanes gives the title product as a syrup (2.15 g, 87.7% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Solvent: CO
Solvent: O
Product: COC(=O)c1coc2c1C(=O)CCC2
Temperature: 25 °C
Yield: 848.6 %

Procedure:
To a solution of 2.11 g of 4-oxo-4,5,6,7tetrahydrobenzo[b]furan-3-carboxylic acid in 100 ml of methanol is added 202 mg of p-toluenesulfonic acid hydrate and the mixture heated at reflux for 24 hours. The reaction mixture is cooled to room temperature and the methanol concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with 30 ml of saturated sodium bicarbonate and 30 ml of brine. The organic layer is dried with Na2SO4, filtered and the filtrate concentrated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 1.75 g of the desired product as a white crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCOCC2)cc1
Reaction time: 1 h

Procedure:
(4-Formyl-benzyl)-carbamic acid tert-butyl ester Compound 15a (555 mg, 2.37 mmol, prepared as described in Far A R, Cho Y L, Rang A, Rudkewich D M, Rebek J, Tetrahedron, 2002, 58(4), 741-756) was added to a solution of morpholine (207 μL, 2.37 mmol) in MeOH (5 mL) and acetic acid (0.20 mL). The mixture was stirred for 1 hr and then 95% NaBH3CN (198 mg, 3.0 mmol) was added. The reaction was diluted after 2 hr with saturated NaHCO3 and extracted with EtOAc to provide (4-morpholin-4-ylmethyl-benzyl)-carbamic acid tert-butyl ester Compound 15b (230 mg), isolated by flash chromatography as a white solid. MS 307 (MH+). Compound 15b (230 mg, 0.752 mmol) was deprotected with 20% TFA in DCM (10 mL) to provide 4-morpholin-4-ylmethyl-benzylamine Compound 15c (63 mg) upon work-up. MS 207 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[C:15](O)(=O)[CH3:16]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH3:16])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: CC(=O)O
Agent: Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCO

Procedure:
A mixture of 20 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 50 parts of acetic acid and 150 parts of a hydrochloric acid solution 4 N is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 5-chloro-2-methyl-1H-benzimidazole-1-propanol.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:42]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([O:40][CH3:41])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)#[N:43]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of methyl 14-cyclohexyl-7(R,S)-({[(4-methylphenyl)sulfonyl]oxy}methyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.35 M) in DMF was treated with NaCN (1.2 eq) and the resulting mixture was stirred overnight at RT. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc. The combined organic layers were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 9:1) affording the product as a yellow foam (90%). (ES+) m/z 429 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31])[CH3:33]
Reactant: CC=O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Reaction time: 1 h

Procedure:
cis-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.177 mmol) was suspended in 1,2-dichloroethane (6 mL). A solution of acetaldehyde (12 mg, 0.266 mmol) in 1,2-dichloroethane (0.300 mL) and acetic acid (42 mg, 0.708 mmol) was added and the mixture was stirred for 1 hour. Sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. After 16 hours, more sodium triacetoxyborohydride (37 mg, 0.175 mmol) was added and the reaction continued for another 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL) then washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (80 mg) was collected as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (102 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.66 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.51-7.60 (m, 7H), 8.55 (s, 1H), 8.66 (s, 1H), 9.26 (s, 1H); LC-MS (ESI) m/z 547 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14][C:15]([C:17]2([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:11][O:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:32][C:17]1([C:15]([NH:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][O:12][CH3:13])=[O:16])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1
Reactant: COCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 48 h
Yield: 97.8 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 1.151 mL, 4.60 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-methoxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 101) (50 mg, 0.09 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 days. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH; pure fractions were evaporated to dryness and the residue was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-3-methoxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (39.0 mg, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[Li].I[CH3:23]>C1COCC1>[CH3:23][C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][C:2]([CH3:20])([CH3:1])[CH2:6][N:5]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CI
Reactant: CCOC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (163D) (10 g, 0.035 mol) in dry THF (60 mL) stirred at −78° C. under nitrogen was added a 1 M solution of lithium hexmethyldisilazide in THF (38.5 mL, 0.038 mol). The mixture was stirred at −78° C. for 30 min, iodomethane (5.4 g, 0.038 mol) in THF (5 mL) was added, and the mixture was then stirred 1 h, warmed up to room temperature and continued stirring for additional 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (10-20% EtOAc/hexanxe) to furnish (163E) (8.2 g, 72%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]=2[CH:20]=1.O>ClCCl>[C:5]([C:12]1[C:13]2[O:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]=2[CH:20]=[C:10]([Br:9])[CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A stirred, cooled (ice-bath) suspension of aluminum chloride (0.25 g, 1.7 mmol) in 3 mL of anhydrous dichloromethane was treated with acetyl chloride (0.2 mL, 2.6 mmol) under argon. A solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 0.22 g) in 1.5 mL of anhydrous dichloromethane was cannulated into the clear solution, and the resulting deep red solution was allowed to warm to ambient temperature over 1 h. The reaction mixture was poured onto iced water and extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a dirty white solid. Flash column chromatography on silica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluent afforded the title compound as a white solid (0.177 g, 67%).