Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:14]1(C)C=CC=C[CH:15]=1.C(O)C.S(=O)(=O)(O)O>O.C(OCC)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2c(c1)CCO2
Reaction time: 6 h

Procedure:
2,3-dihydrobenzofuran-5-ylacetic acid (5.4 g) was heated at reflux in a solution of toluene (200 ml), ethanol (20 ml) and concentrated sulfuric acid (0.5 ml) with the azeotropic removal of water. When the reaction was complete, approximately 6 hours, the mixture was added to water/ethyl acetate and extracted with ethyl acetate. The organic extracts were combined and washed with 10% sodium carbonate, dried over sodium sulfate and the solvent evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[C:5]=2[CH3:16].[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:17].[CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]3[N:24]([CH3:39])[C:25]([C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]5)=[N:26][N:27]=3)[CH2:11][CH2:12][C:6]=1[C:5]=2[CH3:16]
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Reactant: Cc1nc2cc3c(c(C)c2o1)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCCN4CCc5cc6nc(C)oc6c(C)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2,10-dimethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (80 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (153 mg) and was obtained as a colourless slightly hygroscopic solid (146 mg).
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[C:20]([F:19])([F:29])[F:30])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNCc2ccccc2C(F)(F)F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dec-1-ynylbenzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 402.3. HPLC (Condition A), Rt: 4.71 min (HPLC purity: 86.5%).
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:2]([CH3:1])[C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5])(=[O:13])=[O:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 0.22 g of methyl N-methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate in 8 mL of ethyl acetate was added 1.21 g of tin (II) chloride dihydrate and the reaction was stirred at room temperature overnight. To the reaction was added ˜8 mL of 2N sodium carbonate to adjust the pH to ˜8-9. The reaction was then filtered through celite. The filtrate washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide 0.19 g of as methyl N-[(4′-amino-1,1′-biphenyl-4-yl)sulfonyl]-N-methyl-D-valinate as an oil. Yield 95%. MS:377.2 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:18][C@H:17]([C:19]([O:21]C)=O)[CH2:16]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[NH:2]([C:19]([C@H:17]1[CH2:18][C@H:15]([NH:14][C:12](=[O:13])[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16]1)=[O:21])[NH2:3]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (10 ml) was added to a methanol (50 ml) solution of methyl trans-3-{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate (Neurochemical Research, 1980, 5, 393-400) (995 mg, 3.78 mmol) at room temperature and the resulting mixture was stirred for 24 hours. The precipitated solid was collected by filtration, washed with water and then dried to give 760 mg (76%) of the title compound as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]([CH:53]([CH3:55])[CH3:54])[CH2:41][C@H:42]([C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([C@H:42]([C:43](=[O:44])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)[CH2:41][N:40]([CH:53]([CH3:54])[CH3:55])[C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:47][CH:48]=1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.111 mL, 0.636 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.070 g, 0.159 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0543 g, 0.159 mmol, see Example B) and O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium tetrafluoroborate (“TBTU”) (0.0613 g, 0.191 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was then directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.044 g, 48%). MS ESI (+) m/z 503.4 detected.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[F:38])[NH:21][C:22]1[C:31]2[C:30]([OH:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=2[N:25]=[CH:24][N:23]=1.[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59][O:32][C:30]2[CH:29]=[C:28]([O:33][CH3:34])[CH:27]=[C:26]3[C:31]=2[C:22]([NH:21][C:20]2[CH:35]=[CH:36][C:37]([F:38])=[C:18]([Cl:17])[CH:19]=2)=[N:23][CH:24]=[N:25]3)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 914 mg) was added in one portion to a mixture of 4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-ol (848 mg), tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (1.10 g), and triphenylphosphine (1.04 g) in DCM (100 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (839 mg, 50%); Mass spectrum MH+ 633.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH2:12]Br>CO>[Br:11][C:9]1[CH:10]=[C:5]2[C:6]([CH2:12][NH:1][C:4]2=[O:3])=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)ccc1CBr
Solvent: CO
Product: O=C1NCc2ccc(Br)cc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H).
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>C(#N)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:5]2[CH2:6][CH2:7][N:2]([C:8]([O:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[O:9])[CH2:3][CH2:4]2)=[CH:27][CH:28]=1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Reactant: Clc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COC(=O)N1CCN(CCOc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of 0.073 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl piperazine-1-carboxylate hydrochloride, prepared in step 3.3., 0.13 g (0.9 mmol) of potassium carbonate and 0.069 g (0.29 mmol) of 1-(2-bromoethoxy)-4-chlorobenzene in 3 ml of acetonitrile is heated at 85° C. for 16 hours. After cooling to ambient temperature, the inorganic components are filtered off through a cartridge fitted with a frit and containing celite. The cartridge is rinsed with acetone and the filtrate is concentrated under reduced pressure. Chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether give 0.089 g of product in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][C@@H:9]2[CH2:12][C@H:6]1[C:7](=[O:13])[O:8]2)=[O:4].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=[O:23].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][C@@H:9]([OH:8])[CH2:12][C@H:6]1[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2
Reactant: OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a stirred solution of compound 3 (1.85 g, 1 eq.), in dry DMF (10 mL) were added benzyl alcohol (1.25 mL, 1.2 eq.) and K2CO3 (2.8 g, 2 eq.). The reaction mixture was stirred for 16 hrs under nitrogen. Water was then added and the reaction was extracted with TBDME. The combined organic layers were washed with brine, dried over MgSO4, concentrated under reduced pressure, and purified by chromatography on silica gel (DCM/MeOH) to yield compound 4 as beige solid in 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1.FC1C=C(F)C=CC=1CN1C2=CN=C(C(OCC)=O)C=C2C(CO)=C1.C(OCC1C2C(=CN=C([C:67]([NH:69][OH:70])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.Cl.CNO>>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:69]([OH:70])[CH3:67])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1
Reactant: O=C(O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CNO
Agent: Cl
Product: CN(O)C(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
1-(2,4-Difluorobenzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6). δ: 8.96 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 7.29-7.32 (m, 2H), 7.08 (m, 1H), 5.61 (s, 2H), 5.09 (s, 1H), 4.66 (s, 2H). LCMS (API-ES, M+H+): 319.1. (b) 1-(2,4-Difluorobenzyl)-N-hydroxy-3-hydroxymethyl-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ: 8.80 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.29-7.32 (m, 1H), 6.93-7.04 (m, 2H), 5.57 (s, 2H), 4.81 (s, 2H), 3.43 (s, 3H). LCMS (APCI, M+H+): 348.0. HRMS (M+H): 348.1175; cal: 348.1160 with C17H16F2N3O3. HPLC: 96.15% purity.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:2]1.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:16][CH2:13][C:14]#[CH:15])=[O:12])[S:2]1
Reactant: C#CCN
Reactant: O=C(O)CCCC[C@H]1CCSS1
Product: C#CCNC(=O)CCCC[C@H]1CCSS1

Procedure:
In amide coupling reaction (as shown in Scheme 10), (S)-5-(1,2-dithiolan-3-yl)pentanoic acid (11) and prop-2-yn-1-amine perform coupling reaction to form (S)-5-(1,2-dithiolan-3-yl)-N-(prop-2-ynyl)pentanamide (12).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[C:18](=[O:36])[N:19]([C:23]2[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)=[O:27])[CH:20]=[CH:21][N:22]=1.[CH3:37][NH2:38]>O1CCOCC1>[CH:29]1([NH:28][C:26](=[O:27])[C:25]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([N:13]4[CH2:14][CH2:15][CH2:16][CH:12]4[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH2:3][CH2:2][NH:38][CH3:37])[C:18]3=[O:36])[CH:24]=2)[CH2:31][CH2:30]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCCC2c2ccccc2OCCCCl)c1=O
Solvent: C1COCCO1
Product: CNCCCOc1ccccc1C1CCCN1c1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O

Procedure:
3-[3-{2-[2-(3-Chloropropoxy)phenyl]pyrrolidin-1-yl}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide (Example 324b, 0.23 g) and methylamine (1 mL) were heated in a CEM microwave in dioxane at 110° C. for 15 min. The resulting solution was concentrated in vacuo and purification by preparative HPLC (X-Bridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile) gave the title compound as a solid (0.028 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](CC3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43]Br)[CH:38]=1>>[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:11]2[C:10](=[O:33])[CH:9]=[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@@H:2]([NH2:1])[CH2:3]3)[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12]2=[O:23])[CH:38]=1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1

Procedure:
Title compound 24 was prepared by the methods used in the preparation of compound 17, except that 3-bromomethyl-benzoic acid methyl ester was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.99 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 5.44 (s, 1H), 5.12-5.31 (ABq, J=43.7, 15.9 Hz, 2H), 5.08 (s, 2H), 3.90 (s, 3H), 3.31-3.39 (m, 2H), 2.98 (d, J=11.9 Hz, 1H), 2.87 (m, 1H), 2.71 (m, 1H), 2.11 (m, 1H), 1.89 (m, 1 H), 1.73-1.59 (m, 2H). MS (ES) [m+H] calc'd for C26H28N5O4, 474.2; found 474.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C([S:13]Cl)CCC.O1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH2:16]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([OH:8])=[S:13])[CH:4]=1)[CH2:17][CH2:18][CH3:19]
Reactant: C1CCOC1
Reactant: CCCCSCl
Reactant: O=C(O)c1cc[nH]c1
Product: CCCCc1cc(C(O)=S)c[nH]1
Reaction time: 1 h

Procedure:
Under nitrogen, pyrrole 3-carboxylic acid (4.44 g., 40 mmoles) was dissolved in 50 ml. of tetrahydrofuran and the solution cooled in an ice-water bath. A solution of butylsulfenyl chloride (Example 46, estimated to contain 4.96 g., 40 mmoles) was added dropwise. The bath was removed and stirring continued for 1 hour at room temperature. An equal volume of ether was added, the mixture was filtered, and the filtrate evaporated to an oil (8.3 g.). The oil was chromatographed on 250 g. silica gel, with 100 ml. fractions of the ethyl acetate-1/toluene-5/5% acetic acid eluant collected. Fraction 9 was evaporated and triturated with carbon tetrachloride to yield crystalline 5-butylthiopyrrole-3-carboxylic acid (185 mg., m/e 199). Fractions 7-8 and 9-10 were combined, evaporated to gums, and rechromatographed in smaller columns, collecting 8 ml. fractions of the ethyl acetate-1/heptane-2 eluant. An additional 114 mg. of 5-butylthiopyrrole-3-carboxylic acid resulted.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:30])[CH2:16][CH:15]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH2:14][C:13]([CH3:29])([CH3:28])[NH:12]1>O>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH:15]2[CH2:16][C:11]([CH3:30])([CH3:10])[NH:12][C:13]([CH3:29])([CH3:28])[CH2:14]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:14][C:13]([CH3:29])([CH3:28])[NH:12][C:11]([CH3:30])([CH3:10])[CH2:16]2)[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:26])([CH3:27])[CH2:19]2)[N:4]=1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Product: CC1(C)CC(N(c2nc(Cl)nc(N(C3CC(C)(C)NC(C)(C)C3)C3CC(C)(C)NC(C)(C)C3)n2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Following the procedure described in Preparation 11(b), cyanuric chloride was reacted with bis(2,2,6,6-tetramethyl-4-piperidyl)amine [prepared as described in Preparation 12(a)]. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous potassium carbonate and then the chloroform was distilled off. The residue was recrystallized from chloroform, to afford the desired product, in the form of crystals melting at 295° C. (with decomposition).
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([F:15])=[C:7]([C:11]([F:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].S([O-])([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[F:15][C:6]1[C:5]([S:2]([OH:4])=[O:3])=[CH:13][CH:12]=[C:11]([F:14])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(F)ccc(S(=O)(=O)Cl)c1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(F)ccc(S(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
41 mmol of 3-chlorosulfonyl-2,6-difluoro-benzoic acid was slowly added over 20 min. to a solution of 310 mmol sodium sulfite in 200 ml of water. The resulting mixture was stirred for one hour at room temperature, cooled to 0° C. and acidified with 20% aqueous sulfuric acid. The sulfinic acid was extracted with ethyl acetate, dried over MgSO4 and concentrated to yield the title compound as a colorless solid. MS (m/e): 220.9 (M−H, 100%)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:30])[CH:26]=4)[N:21]([CH3:31])[C:20]3=[O:32])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1.C[N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=O.CN(C)C=[O:47]>>[CH3:34][O:33][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:35][CH3:36])[N:3]=[C:2]([N:38]1[CH2:42][CH2:41][O:47][CH2:40][CH2:39]1)[N:11]=[C:10]2[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:30])[CH:26]=3)[N:21]([CH3:31])[C:20]2=[O:32])[CH2:16][CH2:17]1
Reactant: COc1cc2nc(Cl)nc(N3CCC(Cn4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Reactant: CN1CCCC1=O
Reactant: CN(C)C=O
Product: COc1cc2nc(N3CCOCC3)nc(N3CCC(Cn4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 76 %

Procedure:
The same procedure as in Example 1 was repeated, except that 300 mg (0.59 mmol) of 3-[1-(2-chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound h) obtained in Reference Example 9 was used in place of Compound a, and N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, to give 250 mg (yield: 76%) of Compound 27 as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:27]=[N:26][CH:25]=[C:24]([N:28]3[CH2:40][CH2:39][N:31]4[C:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=5[CH:38]=[C:30]4[C:29]3=[O:41])[C:21]=2[CH:22]=[O:23])=[CH:3]1.[BH4-].[Na+]>CO>[OH:23][CH2:22][C:21]1[C:20]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:19]=[C:13]4[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]4[N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:27][N:26]=[CH:25][C:24]=1[N:28]1[CH2:40][CH2:39][N:31]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=3[CH:38]=[C:30]2[C:29]1=[O:41]
Reactant: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A mixture of 138a (200 mg, 0.36 mmol) and NaBH4 (50 mg, 1.2 mmol) in MeOH (60 mL) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc (10 mL×3). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 138 (162 mg, 85%). LCMS: [M+H]+: 555.3. 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.49 (s, 1H), 7.97 (d, J=2.5, 1H), 7.42 (s, 1H), 7.33 (d, J=2, 1H), 6.88 (s, 1H), 5.68 (s, 1H), 4.65-4.63 (m, 1H), 4.57-4.55 (m, 1H), 4.37 (t, J=11, 1H), 4.20-4.16 (m, 3H), 4.07-3.98 (m, 3H), 3.70 (s, 3H), 3.59 (s, 2H), 2.87 (t, J=5.5, 2H), 2.61-2.56 (m, 4H), 2.48 (s, 3H), 1.92-1.90 (m, 2H), 1.80-1.79 (m, 2H)