Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:19])[CH2:12][CH2:11]1.Br[C:36]1[S:37][C:38]2[CH:44]=[C:43]([C:45]([N:47]([CH3:60])[CH2:48][CH2:49][CH2:50][N:51]([CH3:59])[C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:46])[CH:42]=[CH:41][C:39]=2[N:40]=1.C(N(CC)CC)C>C(O)CCC>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:36]2[S:37][C:38]3[CH:44]=[C:43]([C:45](=[O:46])[N:47]([CH2:48][CH2:49][CH2:50][N:51]([C:52]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:58])[CH3:59])[CH3:60])[CH:42]=[CH:41][C:39]=3[N:40]=2)[CH3:19])[CH2:14][CH2:15]1
Reactant: CN(CCCN(C)C(=O)c1ccc2nc(Br)sc2c1)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1nc2ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc2s1
Yield: 63.6 %

Procedure:
The compound (133 mg, 0.298 mmol) obtained in Example 1a and the compound (132 mg, 0.298 mmol) obtained in Example 93b were dissolved in n-butanol (3 mL), triethylamine (62 μL, 0.447 mmol) was added, and the mixture was stirred with heating to reflux for 15 hours. A solution of the compound (133 mg, 0.298 mmol) obtained in Example 1a in n-butanol (2 mL) was added to the reaction mixture, and the mixture was further stirred with heating to reflux for 24 hours. Subsequently, triethylamine (62 μL, 0.447 mmol) was added to the reaction mixture, and the mixture was further stirred with heating to reflux for 24 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→50:1, v/v) to give the title compound (157 mg; yield, 64%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 1). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2--benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(NCc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (0.30 g), 2,4-dichlorobenzyl amine (818 μL), and 1,4-dioxane (3 mL) was stirred at room temperature for 21 hours. To the reaction liquid was added ethyl acetate (30 mL), washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain methyl 2-(2,4-dichlorobenzylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylate (446 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:20][C:21](=[O:40])[CH:22]([NH:32]C(OC(C)(C)C)=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:20][C:21](=[O:40])[CH:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(OC)c(F)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccc(OC)c(F)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2-{(S)-2-[2-tert-Butoxycarbonylamino-2-(3-fluoro-4-methoxy-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (0.98 g, 2.28 mmol) was taken into dry dichloromethane (20 mL) under argon and cooled in an ice bath. To this was added trifluoroacetic acid (10 mL, 130 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then concentrated to dryness. The oil was dissolved in dichloromethane and precipited with ether and the resulting suspension stirred for 15 minutes. The precipitate was isolated by filtration, washed with ether and dried to give a tan solid. The solid was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic solution was dried over sodium sulfate, filtered, concentrated and dried to give 2-{(S)-2-[2-amino-2-(3-fluoro-4-methoxy-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as a tan foam (0.70 g, 92%).
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[CH:8]1[CH:17]=[C:16]2[C:18]([O:20][C:21](=O)[C:14]3=[C:15]2[C:10](=[C:11]([Br:23])[CH:12]=[CH:13]3)[CH:9]=1)=[O:19]>N1C=CC=CC=1>[Br:23][C:11]1[CH:12]=[CH:13][C:14]2[C:21](=[O:20])[N:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:18](=[O:19])[C:16]3[C:15]=2[C:10]=1[CH:9]=[CH:8][CH:17]=3
Reactant: CC(C)(C)ON
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Yield: 94.1 %

Procedure:
O-tert-Butylhydroxylamine hydrochloride (3.0 g, 23.9 mmol) was added to 4-bromo-1,8-naphthalic anhydride (5.0 g, 18.0 mmol) in pyridine (30.0 mL). the mixture was refluxed for 4 hours, concentrated, and the residue suspended in water. The solid was filtered and dried to give 5.9 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 105 %

Procedure:
The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 92 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C16H18FN3, 271.15; found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.47 (m, 2H), 7.31-7.27 (m, 2H), 3.55-3.51 (m, 1H), 3.41-3.39 (m, 2H), 3.23-3.14 (m, 2H), 3.00-2.83 (m, 2H), 0.93-0.084 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14](=[O:23])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:22][C:18]1[CH:17]=[C:16]([NH:15][C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[NH2:7])=[O:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2NC(=O)OC(C)(C)C)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
[2-Methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid tert-butyl ester (0.532 g, 1.53 mmol) was dissolved in 12 mL trifluoroacetic acid and stirred at room temperature for 30 min. The reaction mixture was treated with 2N sodium carbonate solution until pH 10 and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0→0:100 gradient to yield 5-amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide as a light yellow solid (0.361 g, 95%), MS (ISP): m/e=249.1 (M+H+).
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].Cl.Cl.[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH2:39])=[C:32]2[CH:31]=[CH:30]1>>[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:2]3[N:26]=[CH:25][CH:24]=[CH:23][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:9][CH:8]=3)=[O:5])=[C:32]2[CH:31]=[CH:30]1
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1F
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from 2-fluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 510 (M+H). Calc'd. for C23H17F6N5O2—509.41.
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH2:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][CH:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12]3)[C:1]1=[O:15]
Reactant: O=C1CC=Cc2ncc3ccccc3c21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2c(ncc3ccccc23)C=CC1Br
Yield: 91.4 %

Procedure:
99.8 g (511 mmol) phenanthridinone was added to a 3 L multi-neck flask equipped with a stir arm and condenser. 1.2 L glacial acetic acid was added and the mixture was allowed to stir at 150 rpm and heated to reflux. 90 g (562 mmol) Br2 suspended in 100 ml acetic acid was added to the refluxing solution dropwise over a period of 3 hours. After addition, the mixture was assayed and revealed to be ˜80% complete. Based on this assay, an additional 20 g of Br2 (in 30 mL acetic acid) was added dropwise to the mixture at reflux. After this addition, the assay was >90% complete. A final 20 g Br2 (in 30 mL acetic acid) was added dropwise and the mixture allowed to stir for 1 hour after addition. The final assay was >97%. The mixture was cooled and 1 L of water was added and the mixture filtered. The wet solids were then stirred in aqueous sodium thiosulfate to destroy residual bromine and refiltered. These solids were rinsed with H2O and allowed to dry in vacuo to remove residual water. The solids were then recrystalllized from nitrobenzene (>2 liters) and collected on a funnel to give 128 g 2-bromophenanthridinone (90.8% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[CH2:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21].N1CCCCC1>C(O)C>[C:1]([C:3](=[CH:32][C:29]1[CH:28]=[CH:27][C:26]([S:23](=[O:25])(=[O:24])[NH:22][CH2:20][CH3:21])=[CH:31][CH:30]=1)[C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2]
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Reactant: CCNS(=O)(=O)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(C=C(C#N)C(=O)N(c2ccc3nc(S)sc3c2)C(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (71 mg, 0.244 mmol) and N-ethyl-4-formylbenzenesulfonamide (52 mg, 0.244 mmol) were combined in absolute ethanol (1 ml). The mixture was stirred 15 minutes with activated 4A molecular sieves in a sealed vessel. Piperidine (27 μL, 0.268 mmol) was added and the mixture was heated to 80° C. After 1.5 hours, the solution was concentrated in vacuo and purified by preparative TLC (50% ethyl acetate, 50% hexanes) to yield 19 mg (16%). 1H NMR(CDCl3) δ=1.08 (t, 3H), 1.20 (m, 6H), 2.99 (t, 2H), 4.98 (m, 1H), 5.41 (m, 1H), 7.17 (d, 1H), 7.32 (m, 3H), 7.81 (d, 2H), 7.88 (d, 2H), 7.96 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
15.0 g of 2-Bromobenzylamine hydrochloride was dissolved in 100 ml of tetrahydrofuran, and a solution of 13 g of t-butyl dicarbonate in tetrahydrofuran (25 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate, and washed successively with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 16.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C:17]([CH:23]=[O:24])([CH2:20][CH2:21][CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C:17]([CH:23]([C:4]2[S:3][C:2]([Cl:1])=[C:6]([Cl:7])[CH:5]=2)[OH:24])([CH2:20][CH2:21][CH3:22])[CH2:16]1)=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: Clc1ccsc1Cl
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)C1
Product: CCCC1(C(O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-[(4,5-Dichloro-thiophen-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2,3-dichloro-thiophene and 3-formyl-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester using the procedure of step 1 of Example 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1.[CH:16]1([C:19](=O)[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC=CC=1>CC(O)=O>[CH:16]1([C:19]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3[CH:12]=[N:11][N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:14]=3[N:15]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Temperature: 63 °C
Yield: 71 %

Procedure:
A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 g of the desired cyclized product and 1.71 g of the uncyclized adduct. The uncyclized adduct was dissolved in 25 mL of AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford an additional 1.15 g of the desired cyclized product (combined yield=71%). LCMS E-S (M+H)=352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.13 (m, 4 H) 1.38 (t, J=7.07 Hz, 3 H) 2.39 (s, 1 H) 3.67 (s, 3 H) 4.41 (q, J=7.07 Hz, 2 H) 5.51 (s, 2 H) 6.84 (d, J=8.84 Hz, 2 H) 7.21 (d, J=8.59 Hz, 2 H) 7.64 (s, 1 H) 8.23 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:21]([Si:25]([CH3:34])([CH3:33])S(C(F)(F)F)(=O)=O)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH:9]=[C:10]([O:11][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:34])[CH3:33])[C:4]=2[CH:3]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: CC(C)(C)[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1=CCCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (3 g, 12.6 mmol) and triethylamine (10 mL, 18.9 mmol) in DCM (100 mL) was added tert-butyldimethyl(trifluoromethylsulfonyl) silane (3.06 g, 12.4 mmol) dropwise under argon at room temperature, the mixture was stirred for 1 hour at room temperature. The mixture was washed with NaHCO3, dried over Na2SO4, concentrated to give crude (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dim ethylsilane (3.40 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C@@:7]([C@H:16]1[CH2:20][O:19][CH2:18][C@H:17]1[OH:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])[CH3:8].N1C=CC=CC=1.[S:34](Cl)(Cl)=[O:35]>ClCCl>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C@@:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])([CH3:8])[C@@H:16]2[C@@H:17]([CH2:18][O:19][CH2:20]2)[O:21][S:34]1=[O:35]
Reactant: COc1ccc(CN[C@](C)(c2ccccc2F)[C@H]2COC[C@H]2O)c(OC)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CN2S(=O)O[C@@H]3COC[C@@H]3[C@@]2(C)c2ccccc2F)c(OC)c1
Yield: 94.9 %

Procedure:
Under a dry atmosphere of argon, a solution of rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (6.8 g, 18.1 mmol) in pyridine (7.32 ml, 90.5 mmol) and dichloromethane (120 ml) was cooled to −77° C. The colorless solution was treated dropwise with thionyl chloride (2.15 g, 18.1 mmol) over about 10 minutes while the temperature rose to −73° C. After removal of the cooling bath the reaction mixture was allowed to reach room temperature. For the workup, the reaction mixture was diluted with dichloromethane (150 ml) and washed consecutively with hydrochloric acid (1N) and a saturated solution of sodium hydrogencarbonate. The organic layer was dried over sodium sulphate and evaporated. The (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5-oxide (7.24 g, 95% yield) was obtained as a white solid. MS (ISP): m/z=422.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26]([NH2:28])[CH3:27].O1CCCC1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([OH:24])[CH2:25][NH:28][CH2:26][CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@H]2CO2)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC[C@@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 13b) (110 mg), ethylamine (70% aqueous solution, 2 mL) and tetrahydrofuran (10 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The resulting white solid was filtered off to give the titled compound (109 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)OCO2)c1ccccc1

Procedure:
A mixture of 25 g. (0.181 mole) of 3,4-methylenedioxyphenol, 36 g. (0.181 mole) of α-bromoacetophenone and 41.2 g. (0.40 mole) of sodium carbonate in 350 ml. of benzene is heated to its reflux temperature and maintained at reflux for 16 hours. To the mixture is added 50 g. of potassium carbonate, and the mixture is refluxed for an additional 7 days while collecting water in a Barrett water trap. The mixture is then diluted with a mixture of water and benzene. The benzene layer is washed with water, then cold 5 percent sodium hydroxide solution. A precipitate forms in the benzene layer. It is collected, rinsed with benzene and dried to provide a white powder which is recrystallized from ethanol to provide α-(3,4-methylenedioxyphenoxy)acetophenone, m.p. 123°-126° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:12])[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Si:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: C[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccccc1

Procedure:
(2S,3S)-2-(tert-butyldimethylsilyloxy)-5-phenyl-pentan-3-ol was prepared from (S)-2-(tert-butyldimethylsilyloxy)propanal (Synthesis 1996, 652, 3.00 g) and 2-phenylethyl bromide.
Reaction SMILES: [CH2:1]1O[CH:2]1[CH3:3].O[CH2:6][CH:7]([CH2:9]O)O>>[CH2:2]([C:1]1[CH:6]=[CH:7][C:1]([CH2:2][CH3:3])=[CH:6][C:7]=1[CH2:9][CH3:9])[CH3:3]
Reactant: OCC(O)CO
Reactant: CC1CO1
Product: CCc1ccc(CC)c(CC)c1

Procedure:
30 grams of the reaction product of glycerine with propylene oxide to a molecular weight of about 260.