Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:25]([CH3:26])[NH:28][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Reactant: CC(=N)N
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)[nH]c1CC2
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.66 mmol) in 15 mL 1,4-dioxane is added acetamidine hydrochloride (3.32 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. To the residue is added 14 mL CHCl3 and 2 mL MeOH and the mixture is stirred for 10 min. The solid is filtered off. The mother liquid is concentrated and is chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 2-methyl-3,4,5,6-tetrahydro-imidazo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (30%). 1H NMR (DMSO-d6) 1.30 (t, 3H), 2.28 (s, 3H), 2.70 (t, 2H), 2.79 (t, 2H), 4.22 (q, 2H), 7.20 (s, 1H), 10.58 (s, 1H), 11.43 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[OH:24])[CH:19]=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(Cl)c3)nc2c1
Yield: 30 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-chloro-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg, 30%) was isolated as a yellow solid. Selected data: MS (m/z): 333.03; MP 279-281° C.
Reaction SMILES: C(OC([NH:11][CH:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C1C=CC=CC=1.Cl[C:26]1[N:31]=[C:30](Cl)[C:29]([F:33])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[NH:50][C:49](=[O:54])[CH2:48][CH2:47]2>CC#N>[NH2:11][CH:12]([CH:19]1[CH2:20][CH2:21][N:22]([C:28]2[C:29]([F:33])=[CH:30][N:31]=[C:26]([NH:43][C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[NH:50][C:49](=[O:54])[CH2:48][CH2:47]4)[N:27]=2)[CH2:23][CH2:24]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(NC(=O)OCc1ccccc1)C1CCNCC1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(N)C1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Temperature: 25 °C
Reaction time: 68 h
Yield: 47.4 %

Procedure:
To a solution of ethyl 3-(benzyloxycarbonylamino)-3-(piperidin-4-yl)propanoate (102 mg, 0.305 mmol) and 2,4-dichloro-5-fluoropyrimidine (51 mg, 0.305 mmol) in CH3CN (2 mL), DIEA (0.106 mL, 0.610 mmol) was added. The mixture was stirred at room temperature for 68 h. It was then concentrated in vacuo. The residue was dissolved in nBuOH (3 mL), 6-amino-3,4-dihydroquinolin-2(1H)-one (82 mg, 0.506 mmol) was added. The solution was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was dissolved in MeOH (9 mL). To the solution, Pd—C (10%, 40 mg) was added. The mixture was then hydrogenated under balloon hydrogen for 20 h. It was filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (66 mg). MS 457.4 (M+H); UV 211.9, 277.3 nm.
Reaction SMILES: [O:1]=[C:2]([C:8]([O:10][CH2:11]C)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH:14]([CH2:19][OH:20])[C:15]([O:17][CH3:18])=[O:16].[C:21](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-]>CCCCCC>[O:20]1[CH2:19][CH:14]([C:15]([O:17][CH2:18][CH3:21])=[O:16])[O:1][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: COC(=O)C(Br)CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Product: CCOC(=O)C1COC(C(=O)OC)(C(=O)OCC)O1
Reaction time: 8 h

Procedure:
Diethyl ketomalonate 15 g (0.086 mol) and methyl 2-bromo-3-hydroxy-propionate (Example 5a)) were mixed and after returning to room temperature were treated with hexane (50 ml) and 18.6 g (0.134 mol) potassium carbonate. After 6 hours an additional 5.9 g of carbonate was added and the mixture stirred at 45° overnight.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].O1CCCC1.CN(C)C=O>CO>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate, Preparation 31 (573 mg, 2.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (612 mg, 3.0 mmol) according to Method B and Method C. The crude precipitate was formed from dimethylformamide and methanol to give 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 237 mg, 0.563 mmol, 28% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.1 Hz, 1H), 4.95 (dd, J=9.4, 7.0 Hz, 1H), 4.78 (dd, J=10.2, 5.9 Hz, 1H), 4.31 (dd, J=13.3, 10.5 Hz, 1H), 4.00 (ddd, J=13.2, 9.7, 5.7 Hz, 1H), 2.03-2.16 (m, 1H), 1.13-1.68 (m, 8H). ES-MS m/z 422 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by cyclopropanecarbonyl chloride (15 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the product purified by semi-preparative HPLC. Yield 20 mg (95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:30][CH:31]=[CH2:32].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: C=CCc1ccc2c(c1OCCCCCOc1ccccc1/C=C/C(=O)OC)CCCC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc2c(c1OCCCCCOc1ccccc1CCC(=O)OC)CCCC2=O
Yield: 77.7 %

Procedure:
A mixture of 1.72 g (3.84 mmol) of (E)-3-[2-[5-[(5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]phenyl]-2-propenoic acid methyl ester from the preceding experiment, 0.1 g of 10% palladium of carbon, and 50 mL of ethyl acetate was stirred in an atmosphere of hydrogen until gas uptake ceased. The catalyst was filtered with suction on a pad of Celite and the filter cake was washed thoroughly with ethyl acetate. Concentration of the combined filtrate and washes under reduced pressure gave a yellow oil which was chromatographed on 50 g of silica gel. Elution with 4:1 hexane-ether afforded 1.35 g (78%) of 2-[5-[(5-oxo-2-propyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]benzenepropanoic acid methyl ester as a pale-yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 54% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [Cl:1][CH:2]([CH2:14][Cl:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.S(Cl)(Cl)=O.C(Cl)(Cl)Cl.[NH3:24]>C1C=CC=CC=1>[Cl:1][CH:2]([CH2:14][Cl:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:24])=[O:12])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(CCC(Cl)CCl)cn1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1ccc(CCC(Cl)CCl)cn1

Procedure:
10 g of 5-(3,4-dichlorobutyl)picolinic acid was added to the solution of thionyl chloride (30 ml) and chloroform (100 ml), and resulting solution was refluxed for fifteen minutes. The reaction mixture was evaporated in reduced pressure to obtain oily residue. This was dissolved in 100 ml of benzene and treated with 28% aqueous ammonia (50 ml) at 4° - 10°C with vigorous stirring for an hour. Benzene extract was evaporated in reduced pressure to give crude product as solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC(CO)=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCc1ccncc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipatate was collected through filtration under nitrogen to give 4-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.91(m, 2H), 2.16(m, 2H), 3.55(m, 2H), 3.90(s, 3H), 4.03 (m, 2H), 4.92(m, 1H), 5.34(s, 2H), 7.06(d, J=8.2 Hz, 1H), 7.16(s, 1H), 7.73(m, 1H), 7.81(m, 1H), 7.87(s, 1H), 8.46(s, 1H), 8.76(d, J=5.6 Hz, 1H), 9.05(s, 1H). LC/MS: MH30 =475.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15](B(O)O)=[C:14]([O:23][CH3:24])[CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:25][O:26][C:27](=[O:55])[C@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][C:44](OS(C(F)(F)F)(=O)=O)=[CH:43][CH:42]=1)[NH:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38]>>[CH3:25][O:26][C:27](=[O:55])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:15]2[C:16]([O:18][CH3:19])=[CH:17][C:12]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:13][C:14]=2[O:23][CH3:24])=[CH:45][CH:46]=1)[NH:29][C:30](=[O:39])[C:31]1[C:32]([Cl:38])=[CH:33][CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: C=CCN(C(=O)OC(C)(C)C)c1cc(OC)c(B(O)O)c(OC)c1
Product: C=CCN(C(=O)OC(C)(C)C)c1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(OC)c1

Procedure:
4-(N-Allyl-N-tert-butoxycarbonylamino)-2,6-dimethoxybenzeneboronic acid and N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester were coupled by a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[4-(N-allyl-N-tert-butoxycarbonylamino)-2,6-dimethoxyphenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][N:16]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:15]2)=[CH:11][CH:10]=1.S(OC)(OC)(=O)=O.O>O1CCCC1>[CH3:1][N:25]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:34])([F:7])[F:35])=[CH:33][CH:32]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)[C:26](=[O:31])[C:27]([F:28])([F:29])[F:30]
Reactant: CC(C)(C)[O-]
Reactant: O=C(NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C(F)(F)F)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
Potassium-t-butoxide (1.4 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepin-3-yl]-trifluoroacet amide (4 g) in 100 mL tetrahydrofuran. After thirty minutes, dimethyl sulfate (1.5 g) was added. After warming to ambient temperature, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated to 4.1 g solid, mp 210°-212°. A 2.5 g portion was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 216°-218°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH:9]=[CH:10][O:11][C:5]=2[CH:4]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:7](=[O:12])[C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][CH:10]=[CH:9]1
Reactant: BrCCCCBr
Reactant: COc1ccc2c(c1)OC=CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=CN(CCCCBr)C2=O
Reaction time: 0.5 h

Procedure:
200 mg of 4,5-dihydro-8-methoxy-1,4-benzoxazepin-5-one was dissolved in 10 ml of dimethylformamide, then 50 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 790 mg (3 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[CH2:7]([N+:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[CH2:20]([N+:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: C=CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: C=CC(=O)[O-]
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A 5 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum were purged with nitrogen. Operating in an atmosphere of nitrogen, 297 grams of poly(isobutylene-co-para-bromomethylstyrene) (Mv=1.2 M, 1.7% para-bromomethylstyrene) was placed into the vessel along with 3.5 liters of xylenes. The polymer was dissolved with stirring under a partial vacuum of 100 mm Hg with a nitrogen sparge attached at the bottom of the solution. A xylene solution of tetrabutylammonium acrylate was prepared in a second flask under nitrogen by placing 100 ml xylenes, 60 ml tetrabutylammonium hydroxide (1 M in methanol) and 6.0 g acrylic acid together with stirring. The contents of the flask was concentrated to half its volume and then diluted to 0.5 liters with more xylenes. This solution was then added to the flask containing the poly(isobutylene-co-para-bromomethylstyrene) and the temperature of the solution was raised to 65° C. The reaction was complete in six hours and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg, 40° C. The analysis for the acrylate content (FTIR and NMR) indicate that the modified polymer has 0.24 meq/gram which is consistent with the complete conversion of acrylic acid to acrylic ester and total conversion of the benzylbromide.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH2:8][CH2:9][CH2:10][SH:11].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH2:10][CH2:9][NH2:8])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: NCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added DMF (10 ml), 2-aminoethanethiol (620 mg, 8 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred at 100° C. for 3 hours. After addition of saturated brine the reaction mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (10% methanol/chloroform) to give the subject compound (126 mg, yield 54%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH3:27]>CO>[CH3:17][C:15]1[NH:27][C:15]([CH3:17])=[C:14]([C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:14]=1[C:13]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: N
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CO
Product: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)C(C(=O)OCc2ccccc2)=C(C)N1
Temperature: 90 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
In a 7% ammonia solution in methanol were dissolved 2.6 g of o-trifluoromethylbenzaldehyde and 5.8 g of benzyl acetoacetate, and the solution was stirred in a closed tube at 90° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane=1/50) to obtain 6.0 g (yield: 76%) of dibenzyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinedicarboxylate as a yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:10]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18]2[C:13](=[C:14]([O:22]CC3C=CC=CC=3)[CH:15]=[C:16]([CH:20]=O)[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]>>[CH2:8]([C:10]1([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:19][C:18]2[C:13](=[C:14]([OH:22])[CH:15]=[C:16]([CH2:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]
Reactant: CCC1(Cc2ccccc2)CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CCc1cc(O)c2c(c1)CC(CC)(Cc1ccccc1)CC2=O

Procedure:
Ethyl bromoacetate is converted to the triphenyl phosphorone, reacted with the product of Example 36 and reduced catalytically to the desired compound using procedures analogous to those described in Example 24.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23].[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23])[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)NS(N)(=O)=O
Reactant: Cc1c(CO)sc2cncn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1sc2cncn2c1C)S(N)(=O)=O
Reaction time: 1.83 h
Yield: 29.1 %

Procedure:
Under an argon atmosphere at -37° C., 0.51 ml of diethyl azodicarboxylate was added dropwise to 6.7 ml of an anhydrous tetrahydrofuran solution containing 365 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole, 586 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 854 mg of triphenylphosphine, and the mixture was then stirred at -37° C. to -20° C. for 110 minutes. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then suspended in 50 ml of dichloromethane. Further, the suspension was extracted with 2N hydrochloric acid (15 ml×2), and the combined aqueous layer was then washed with 20 ml of dichloromethane. After alkalified with anhydrous potassium carbonate, the solution was further extracted with dichloromethane (30 ml×3). The combined organic layer was washed with a semi-saturated saline solution, dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1), and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 208.5 mg of the title compound as a milky white powder.