Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH3:34])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: Cc1ccccc1CBr
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1CN1C(=O)C(=O)c2cc(Br)ccc21
Yield: 53 %

Procedure:
Combine 5-bromoisatin (90 mg, 0.4 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polysteyrene (270-290 mg, 0.60-0.64 mmol, 2.2 mmol/g, Fluka) and 2-methylbenzyl bromide (0.054 mL, 0.4 mmol) in acetonitrile (4 mL) in a 20 dram scintillation vial and shake on a rotator for 2.5 days. Dilute with and a small amount of CH2Cl2 as needed to soluabilize solids. Filter off beads, washing with MeOH, and concentrate in vacuo. Triturate the resulting solid with diethyl ether (about 4 mL) and pipet off the liquid. Dry the solid to obtain approximately 70 mg of the title compound as crude material and use without further purification.
Reaction SMILES: [NH3:1].[Br:2][CH2:3][C:4]1[C:5]([F:21])=[C:6]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[F:20])[C:7]([Cl:10])=[CH:8][CH:9]=1>C(Cl)Cl>[BrH:2].[NH2:1][CH2:3][C:4]1[C:5]([F:21])=[C:6]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[F:20])[C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(Oc2c(Cl)ccc(CBr)c2F)c(F)c1
Reactant: N
Solvent: ClCCl
Product: Br
Product: N#Cc1ccc(Oc2c(Cl)ccc(CN)c2F)c(F)c1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of ammonia (7.0 N solution in MeOH) (47.5 ml, 332 mmol) was added dropwise 4-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (1.49 g, 4.16 mmol) in solution of 20 mL DCM. The mixture was stirred overnight and the solvent was removed to give 4-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile hydrobromide (1.26 g, 3.35 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 8.10 (dd, 1H), 7.66 (d, 1H), 7.57-7.63 (m, 1H), 7.54 (t, 1H), 7.02 (br. s., 2H), 6.93 (t, 1H), 4.00 (s, 2H). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (dd, 1H), 7.66 (d, 1H), 7.57-7.63 (m, 1H), 7.54 (t, 1H), 7.02 (br. s., 2H), 6.93 (t, 1H), 4.00 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=C[CH:11]=1.Cl.[NH2:17][OH:18]>C(O)C>[CH3:11][O:18][N:17]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH3:1]
Reactant: c1ccncc1
Reactant: NO
Reactant: CCCCCC(=O)CC
Agent: Cl
Solvent: CCO
Product: CCCCCC(CC)=NOC
Temperature: 25 °C

Procedure:
To a solution of 8-benzylbicyclo[3.2.1.]octan-3-one (13.66 g) in ethanol (250 ml) was added pyridine (5.69 ml) followed by hydroxylamine hydrochloride (4.85 g) and the resulting mixture was refluxed for 18 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between water and dichloromethane. The organic layer was dried and evaporated to give the title compound as a brown solid which was used without further purification. Yield 10.79 g. MS 231 MH+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:17]=[CH:16][C:9]([C:10]([NH:12][CH2:13][CH2:14][OH:15])=[O:11])=[CH:8][CH:7]=1)=[O:4].[S:18]1C=CC=C1CC([O-])=O.[K+].[CH3:28][C:29](C)=[O:30]>>[C:29]([S:18][CH2:2][C:3]([NH:5][C:6]1[CH:17]=[CH:16][C:9]([C:10]([NH:12][CH2:13][CH2:14][OH:15])=[O:11])=[CH:8][CH:7]=1)=[O:4])(=[O:30])[CH3:28]
Reactant: O=C(CCl)Nc1ccc(C(=O)NCCO)cc1
Reactant: O=C([O-])Cc1cccs1
Reactant: CC(C)=O
Agent: [K+]
Product: CC(=O)SCC(=O)Nc1ccc(C(=O)NCCO)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 4-(2-chloroacetamido)-N-(2-hydroxyethyl)benzamide (39.3 g., 0.153 mole) and potassium thiolacetate (18.3 g., 0.16 mole) in 650 ml. of acetone is heated at reflux temperature for a period of 2 hr. After standing overnight, the reaction mixture is filtered, the filtercake washed with acetone, slurried with water, filtered and the filtercake washed with water and dried to afford 34.7 g. of crude product. Crystallization of this material from ethyl acetate-methanol affords analytically pure 4-[2-(ACETYLTHIO)ACETAMIDO]-N-(2-HYDROXYETHYL)BENZAMIDE, m.p. 190.0°-192.0° C. (corr.) in 57% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([NH2:13])[CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:34]1C(=O)CCC1=O.CCOC(/N=N/C(OCC)=O)=O.[C:53](N)([CH3:56])([CH3:55])[CH3:54]>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:34])=[O:10])=[C:6]([NH2:13])[C:5]=1[C:53]([CH3:56])([CH3:55])[CH3:54])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)N
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1c([N+](=O)[O-])ccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolve 4-nitro-2-aminobenzoic acid (500 mg, 2.75 mmol) in tetrahydrofuran (10 mL). Add triphenylphosphine (730 mg, 2.75 mL) and N-hydroxysuccinimide (316 mg, 2.75 mmol). Add a solution of diethylazodicarboxylate (0.433 mL,2.75 mmol) and stir at room temperature under nitrogen for 10 minutes. Add tert-butylamine (1.1 mL, 5.5 mmol) in tetrahydrofuran (5 mL) directly to the reaction to yield after workup the 4-nitro-2-amino-tert-butylbenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]C(=O)C)[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].ClCCl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(C)=O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2S,4R)-4-acetylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (12.5 g, 41 mmol; CAS Reg. No. 188111-18-4) in MeOH (200 ml) and dichloromethane (20 ml) was added potassium carbonate (5.7 g, 41.2 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. After the starting material was consumed the solvent was evaporated. The residue was dissolved in water and extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to get the crude title compound (9.5 g, 36.1 mmol; 88%) which was used in next step without further purification. MS (ESI): m/z=262.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].CO.O>C(N(CC)CC)C>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), methanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C., and triethylamine was added thereto so as to adjust the pH of the mixture at 9.0-9.3. Six hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C., and methanol was added thereto so that the mixture dissolves. The resultant mixture was cooled for crystallization, to thereby obtain 62.4 g of p-cyanobenzoic acid crystal (purity 97.8%, yield 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](N2S(=O)(=O)NC(=O)C2)=[CH:11][C:12]2[CH2:13][CH2:14][CH:15]([OH:19])[CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C([N:40]2[S:44](=[O:46])(=[O:45])[NH:43][C:42](=[O:47])[CH2:41]2)=CC2CCC(O)CC=2C=1.Cl[CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:53]2[C:52]([CH2:51][O:50][CH2:49][N:43]3[C:42](=[O:47])[CH2:41][NH:40][S:44]3(=[O:45])=[O:46])=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:11][C:12]2[CH2:13][CH2:14][CH:15]([OH:19])[CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1CN(c2cc3c(cc2O)CC(O)CC3)S(=O)(=O)N1
Reactant: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CNS(=O)(=O)N1COCc1ccccc1-c1cc2c(cc1OCc1ccccc1)CC(O)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-benzyloxy-6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (158 mg, 0.40 mmol), intermediate from Example 45, chloromethoxymethylbenzene (0.068 mL, 0.49 mmol) and potassium carbonate (110 mg, 0.80 mmol) in DMF (4 mL) is stirred at RT for 18 h. The mixture is partitioned between EtOAc and 1 N HCl solution. The organic extract is dried with MgSO4 and concentrated. The residue is purified by chromatography to give the title compound as an oil: (M+NH4)+=526.
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC(Cl)=C.Cl>O>[Cl:9][C:10]1[CH2:15][C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]=2[CH2:12][CH:11]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: O=C1C=C(Cl)C(=O)O1
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 105 °C

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing addition funnel, a thermocouple well with thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 13.2 g (0.10 mol) of a 90/10 GC area % mixture of monochloromaleic anhydride and dichloromaleic anhydride and 50 mg of phenothiazine. The contents of the flask were heated to 80 to 130° C. and 8.8 g (0.1 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 6 hours at 130° C. the contents of the flask were multiple distilled into two fractions resulting in the isolation of 12.08 g of 4-chloro-3,6-dihydrophthalic anhydride which was identified by 13C 1H NMR and MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:21]
Reactant: OCCc1cc(Cl)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc(Cl)ccc1Br
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(2-bromo-5-chloro-phenyl)ethanol (1.65 g, 7.00 mmol) [as prepared in preparation 6] and triethylamine (922 mg, 1.27 mL, 9.11 mmol) in DCM (20 mL) was cooled to 0° C. and methanesulfonyl chloride (883 mg, 597 μL, 7.71 mmol) was added. The mixture was stirred for 2 h and then diluted with DCM and washed sequentially with water and brine, the organic layer dried (MgSO4) and concentrated to afford 2-bromo-5-chlorophenethyl methanesulfonate as a yellow solid (2.11 g, 96%). 1H NMR (500 MHz, d6-DMSO) δ 7.67 (1H, d), 7.55 (1H, s), 7.32 (1H, d), 4.44 (2H, t), 3.13-3.36 (5H, m).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: COC(=O)C(OC)OC
Reactant: NCc1ccc(Cl)cc1
Product: COC(OC)C(=O)NCc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Into a vial was added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 4-chlorobenzylamine (1.0 g, 7.3 mmol), this mixture was stirred at 50° C. for 2 d. The product was recrystallized from Heptane to yield the desired product as an oil that solidified over time. MS (ES+): m/z=244.09/246.05 [MH+]. HPLC: tR=2.80 min (ZQ2, polar—5 min).
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O.CN(C)C=O>[C:28]([C@@:2]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 250 mL flask was added 2'-deoxyguanosine monohydrate (5.0 g, 17.5 mmol), triethylamine (3.13 ml, 22.4 mmol) and N,N-dimethyl-4-aminopyridine (0.046 g, 0.37 mmol). N,N-dimethylformamide (130 mL) was added via cannula with stirring and the flask was purged with argon gas. The slurry was allowed to cool 10 minutes in an ice/NaCl bath and palmitoyl chloride (6.3 mL, 20.6 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25 degrees C. After 72 h, the mixture was poured with stirring into 400 mL of a 1:1 mixture of water and saturated aqueous sodium bicarbonate solution, which mixture had been warmed to about 60 degrees C. The resulting white solid was isolated by suction filtration, washed with water, and dried.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.13 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine. The reaction medium is agitated at ambient temperature then taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for four hours at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc2cccc(O)c2n1
Product: COc1ccc(C=Cc2ccc3cccc(O)c3n2)cc1
Temperature: 180 °C

Procedure:
A mixture of 8-hydroxyquinaldine (9.93 g) and p-anisaldehyde (20 mL) is heated at 180° C. overnight. The reaction is then cooled to room temperature and vacuum distilled. Once the majority of the p-anisaldehyde is distilled off (below 100° C. ), the residue remaining in the flask is taken up in hot 95% EtOH. Any undissolved material is filtered off. H2O is added to the EtOH filtrate and the product is obtained as a yellow solid (3.42 g).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][N:8]([CH:10](OC)OC)[CH3:9]>>[CH3:7][N:8]([CH3:10])/[CH:9]=[CH:3]/[CH:2]([CH3:4])[C:1]([NH2:6])=[O:5]
Reactant: CC(C)C(N)=O
Reactant: COC(OC)N(C)C
Product: CC(/C=C/N(C)C)C(N)=O

Procedure:
Following the procedure for 449, Step 3, isobutyramide was reacted with DMF-DMA to afford the title compound as a yellow oil. 1H NMR (CDCl3): 8.39 (1 H, s), 3.10 (3 H, m), 3.07 (3 H, d, J=0.67 Hz), 2.68-2.56 (1 H, m), 1.17 (3 H, s), 1.18-1.11 (3 H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)=[CH:18][C:17]=1[CH3:29].[BH4-].[Na+].O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][CH:3]1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([CH3:29])=[CH:18][C:19]([C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCc1cc2cccnc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCC1Cc2cccnc2N1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 1-methyl-2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-7-azaindole (580 mg, 1.49 mmol) in 16.5 ml of trifluoroacetic acid was added in portions at 0° C. 1.88 g (29.7 mmol) of sodium borohydride. The mixture was stirred at 20° C. for 30 min and then heated at 55°-60° C. for 72 h. To the above mixture was added water, 2N NaOH solution (to pH=8), and the resulting mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, methylene chloride/acetone, 30/1-6/1) to yield 193 mg (33%) of 1-methyl-2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-2,3-dihydro-7-azaindole, as a solid, m.p. 54°-57° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.[CH:21]1([O:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH:35](OCC)OCC)=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>O.CN(C=O)C>[CH:21]1([O:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:34]=[CH:35][N:1]([C@H:2]4[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]4)[C:14]3=[O:15])=[CH:31][CH:32]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(CNc1ccc(OC2CCCC2)cc1)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1n(-c2ccc(OC3CCCC3)cc2)ccn1[C@H]1CC[C@H](O)CC1
Reaction time: 12 h

Procedure:
Trans-4-aminocyclohexanol was reacted by method B with CDI and (4-cyclopentyloxyphenyl)(2,2-diethoxyethyl)amine. The isolated crude product was mixed with DMF (2 ml) and TFA (2 ml) and left to stand for 12 hours. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 342.44 (C20H26N2O3) was obtained in this way; MS (ESI): 343 ([M+H]+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([CH:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:11]#[N:12])[CH:7]=[CH:6][C:5]=1[N+:22]([O-])=O)[CH3:2].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:22][C:5]1[CH:6]=[CH:7][C:8]([CH:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:11]#[N:12])=[N:9][C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CCSc1nc(C(C#N)C(=O)c2ccccc2F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1nc(C(C#N)C(=O)c2ccccc2F)ccc1N
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A solution of 2-(6-(ethylthio)-5-nitropyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile (0.40 g, 1.16 mmol, 1.0 eq.) and SnCl2.2H2O (1.35 g, 5.98 mmol, 5.2 eq.) in EtOAc (30 mL) was refluxed for 0.75 hr and cooled to room temperature. At 0° C., aqueous NaOH (1N, 15 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (10:0.2) as eluent afforded 2-(5-amino-6-(ethylthio)pyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile as a light brown solid (0.1933 g, 53%).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36]([NH:42][C:43](=[O:48])[CH2:44][N:45]([CH3:47])[CH3:46])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].[NH4+:49].[OH-].C(Cl)(Cl)Cl>C1COCC1.FC(F)(F)CO>[CH3:46][N:45]([CH3:47])[CH2:44][C:43]([NH:42][C:36]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([NH:33][C:3]2[N:16]=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH2:49])=[O:17])[C:6]3[CH:19]=[CH:20][N:21]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:5]=3[N:4]=2)[CH:35]=1)=[O:48]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1ccc(NC(=O)CN(C)C)cc1N
Agent: Cl
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: COc1ccc(NC(=O)CN(C)C)cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 80 °C
Yield: 67 %

Procedure:
A slurry of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (400 mg, 0.835 mmol) and N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide hydrogen chloride (217 mg, 0.835 mmol) in THF (15 mL) in 2,2,2-trifluoroethanol (40 mL) was stirred at rt for 3 days. LCMS indicated incomplete reaction, therefore more N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide hydrogen chloride (115 mg, 0.24 mmol) was added and the reaction mixture was heated at 80° C. for 4 h. After allowing to cool to rt the reaction mixture was diluted with THF (100 mL) and a 27% aqueous NH4OH solution (100 mL) and stirred at rt. After 20 h CHCl3 (200 mL) was added. The organic layer was washed with a saturated NaCl solution (100 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-({2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a white solid (364 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 6H), 2.32 (s, 3H), 3.03 (s, 2H), 3.81 (s, 3H), 6.60 (d, J=4.03 Hz, 1H), 6.97-7.07 (m, 2H), 7.30-7.46 (m, 4H), 7.51 (dd, J=8.79, 2.56 Hz, 1H), 7.87-8.03 (m, 6H), 8.35 (br s, 1H), 9.50 (s, 1H), 10.38 (s, 1H); ESIMS (M+H)+=647.