Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12].[CH:14]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[CH:14]1([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]C1CCCC1
Reactant: C#CCCC(=O)Sc1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: C#CCCC(=O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of pent-4-ynethioic acid S-pyridin-2-yl ester (17.9 g, 94 mmol), dissolved in THF (900 mL) cooled to −78° C. was added cyclopentylmagnesium bromide (2.0 M, 94 mL, 188.5 mmol). The reaction was stirred for 15 minutes, and then warmed to −50° C. The reaction was poured into 500 mL 1 N HCl and the layers were separated. The aqueous layer was extracted with 2×200 mL diethyl ether and the organic layers were combined. The organics were then washed with 300 mL of 1 N NaOH. The organic layer was dried over Mg SO4, and the solids were removed by filtration. The solvent was removed by rotary evaporation to give the desired compound (14.0 g, 99% yield). 1H NMR (CDCl3) δ: 1.54-1.87 (m, 8H), 1.94 (t, J=2.65 Hz, 1H), 2.45 (dt, J1=7.33 Hz, J2=2.78 Hz, 2H), 2.71 (t, J=7.58 Hz, 2H), 2.87 (p, J=7.96 Hz, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH:40][C:41](=[O:43])[CH3:42])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH:40][C:41](=[O:43])[CH3:42])=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.46 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetoamidophenylthio)imidazole in 100 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.96 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetamidophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][NH:41][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:26]=[CH:27][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:1])([CH3:31])[CH3:32])=[C:7]([CH3:29])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCC(CC)(c1ccc(OCC(=O)NOCc2ccccc2)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of acid compound 6 (27.4 mg, 0.0622 mmol) in DMF (0.1 mL) was added BnONH2, (10.5 mg, 0.0653 mmol, 1.05 equiv.), followed by iPr2NEt (33 μL, 24 mg, 0.1866 mmol, 3.0 equiv.) and HBTU (25.6 mg, 0.0684 mmol, 1.1 equiv.). After 2 h, the reaction was quenched by the addition of brine and then extracted with EtOAc (×4). The combined organic phases were stirred with triethylamine resin, dried over Na2SO4 and concentrated in vacuo to give a crude product which was subsequently purified by preparative tlc (10:90 acetone/toluene). This afforded the title compound 7 (27.7 mg, 82%)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Product: Cc1cccc(C(=O)NCC2(c3ccccc3)CCN(C)CC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH30 ) m/z=337.0, tR (minutes, Method A)=0.65
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)C[CH2:15]3)=[O:11])=[CH:2]1.N12CC([CH2:29][OH:30])(CC1)CC2>>[CH3:29][O:30][C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:10]([O:12][CH2:13][C:14]34[CH2:15][N:17]([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)=[O:11])=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: OCC12CCN(CC1)C2
Product: COc1ccc2c(C(=O)OCC34CCN(CC3)C4)c[nH]c2c1

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethyl 6-methoxy-1H-indole-3-carboxylate was synthesized using the procedure described for (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate using 1-Azabicyclo[2.2.1]heptan-4-ylmethanol. MS: (m/e) 300.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)[OH:10]>C(Cl)Cl.[O-2].[Mn+4].[O-2].O=[Mn]=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=[N:13][CH:12]=1)=[O:10]
Reactant: Cc1cccc(C(O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 60 °C
Yield: 62 %

Procedure:
A mixture of (2,3-dimethylphenyl)(1-trityl-IH-imidazol-5-yl)methanol, (Intermediate 6) (2.4 g, 7.4 mmol) in CH2Cl2 (60 mL) was treated with manganese (IV) oxide, activated (commercially available from Aldrich): MnO2 (2.8 g, 32.3 mmol) at room temperature. The mixture was heated at 60° C. for 2 hours. The mixture was then cooled to room temperature and filtered through celite and the solvent was removed under vacuum. The residue was purified by MPLC with 3 to 5% MeOH:CH2Cl2 to give (2,3-dimethylphenyl)(I-trityl-IH-imidazol-5-yl)methanone, (Intermediate 7), 1.48 g, (62%).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH2:12][C:11]1([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.[OH:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28]([CH3:42])([CH3:41])[CH2:27]1.[H-].[Na+]>>[CH:1]1([O:9][N:10]2[C:15]([CH3:16])([CH3:17])[CH2:14][CH:13]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][O:25][CH:26]3[CH2:31][C:30]([CH3:32])([CH3:33])[N:29]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[C:28]([CH3:42])([CH3:41])[CH2:27]3)[CH2:12][C:11]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)CC(OCC(O)COC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared by the reaction of 1-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yloxy)-2,3-epoxypropane (prepared in Example 11) with 4-hydroxy-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5) and sodium hydride.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2C([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+].CC(O)=O>O.Cl>[N+:16]([C:5]1[CH:6]=[C:7]([C:14]([OH:15])=[O:13])[C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][CH:9]=2)([O-:18])=[O:17]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Yield: 61.6 %

Procedure:
To a solution of 3-nitro-1,8-naphthalic anhydride (21.8 g, 89.7 mmol) in H2O (550 mL) containing 14.4 g of NaOH was added a solution of yellow HgO (25.1 g) in a mixture of H2O (75 mL) and glacial AcOH (25 mL). After reflux for 4 days, the reaction mixture was cooled and filtered to afford the mercurated product, which was then refluxed in 700 mL of 5N HCl for 3 h. The cream-colored precipitate was filtered, washed with cold H2O, dried, and recrystallized from hot glacial AcOH to yield 3-nitronaphthalene-1-carboxylic acid (12 g). 1H NMR (300 MHz, DMSO-d6): δ 13.7 (brs, 1H), 9.18 (s, 1H), 8.93 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.76 (t, J=6.9 Hz, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.C([O-])(O)=O.[Na+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([NH2:4])[CH:6]=1)[CH3:20]
Reactant: CCO
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccnc(N)c1
Yield: 79 %

Procedure:
2-Acetylamino-isonicotinic acid (10.8 g, 60.0 mmol) was suspended in ethanol (150 mL) and BF3OEt2 (22 mL, 138 mmol) was added. The mixture was refluxed overnight, and after cooling to room temperature 10% NaHCO3 (250 mL) was added. The product was extracted with chloroform and the combined organic extracts were washed with water and dried. Filtering and concentration afforded 2-amino-isonicotinic acid ethyl ester (7.46 g, 79%) as pale yellow crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([N:14]1[CH2:24][CH2:23][C:17]2[N:18]=[N:19][C:20]([SH:22])=[CH:21][C:16]=2[CH2:15]1)=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:11][C:12]([N:14]1[CH2:24][CH2:23][C:17]2[N:18]=[N:19][C:20]([S:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:16]=2[CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2nnc(SCc3ccccc3)cc2C1
Reaction time: 20 h

Procedure:
A mixture of 13.2 g of benzyl bromide in 75 cc of dimethyl formamide is added dropwise within 2 hours to a suspension heated to 50° of 18.5 g of 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 12.8 g of potassium carbonate in 200 cc of dimethyl formamide. The mixture is subsequently stirred at the same temperature for 20 hours and is then completely concentrated in a vacuum. The residue is divided between 200 cc of chloroform and 50 cc of water, the organic phase is separated and concentrated to a dark oil in a vacuum. This is chromatographed on an aluminum oxide column, and elution is effected with a mixture of benzene/petroleum ether 2:1. The crude oily 3-benzylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, obtained after concentrating the eluate, crystallizes from 75 cc of ether after the addition of 25 cc of petroleum ether.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Yield: 80 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 25 mg of (2S,4R)-1-acetyl-2-methyl-4-[(3-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (compound 179) and aqueous ammonia. Thus, 20 mg (80%) of the title compound was obtained as a light yellow oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>>[CH3:14][C:5]1[O:4][C:3]([CH2:2][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:19])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1oc(CCl)nc1-c1ccccc1
Product: Cc1oc(COc2ccccc2C=O)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 2-chloromethyl-5-methyl-4-phenyloxazole was allowed to o-hydroxybenzaldehyde to give 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.95°-96° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>O1CCOCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:35]3=[O:36])[N:12]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 110 °C
Yield: 55.3 %

Procedure:
A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (75 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in 1,4-dioxane (1 mL) was heated at 110° C. for 3 h. After cooling to ambient temperature, the mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 99:1 to 98:2) to afford 183 as a cream solid (45 mg, 57%). LCMS (Method G): RT=6.72 min, M+H+=509. 1H NMR (CDCl3, 400 MHz) δ 8.71 (s, 1 H); 7.77 (m, 1 H); 7.15-7.05 (m, 3 H); 4.42 (m, 4 H); 4.01 (s, 2 H); 3.86 (m, 4 H); 3.71 (m, 6 H); 3.15 (s, 3 H) and 2.36 (m, 4 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:34]2[C:29]3[C:30](=[CH:35][CH:36]=[CH:37][C:28]=3[C:27]1=[O:38])[CH:31]=[CH:32][CH:33]=2)[C:24]#[CH:25].O.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:34]4[C:29]5[C:30](=[CH:35][CH:36]=[CH:37][C:28]=5[C:27]3=[O:38])[CH:31]=[CH:32][CH:33]=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)c2cccc3cccc1c23
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)c4cccc5cccc3c45)cc1C(c1ccccc1Cl)=NC2

Procedure:
Reaction of 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine with 1-(2-propynyl)-benz[cd]indol-2(1H)-one as described in Example 37 yielded after chromatographic purification and slow crystallization from ethyl acetate yellow crystals with m.p. 202°-205° C. These crystals contained according to analytical data 0.75 mol of water. Treatment of this product with ethanolic hydrogen chloride and addition of ethyl acetate gave a crystalline hydrochloride of the title compound with m.p. 219°-222° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:22]=[C:23]=[O:24])[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]>CN(C)C=O>[C:14]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5.5 g of 2,6-xylyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>>[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@H:12]4[N:8]5[C:9]6[C:4](=[CH:3][CH:2]=[CH:1][C:10]=6[C@H:11]4[CH2:16]3)[CH2:5][CH2:6][CH2:7]5)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2c(CCCN3CC[C@@H]4[C@H](C3)c3cccc5c3N4CCC5)noc2c1
Yield: 31.9 %

Procedure:
The title compound (0.15 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.80-2.18 (m, 7H), 2.25 (td, J=11.5, 3.0 Hz, 1H), 2.35-2.68 (m, 4H), 2.70 (t, J=6.6 Hz, 2H), 2.75-2.88 (m, 1H), 3.01 (t, J=7.6 Hz, 2H), 3.05-3.15 (m, 1H), 3.20-3.30 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 7.06 (td, J=9.0, 2.1 Hz, 1H), 7.20-7.26 (m, 1H), 7.61 (dd, J=4.8, 8.7 Hz, 1H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6]([C:7]1[NH:11][CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 900 mg (4.11 mmol) of 2-(2-methylaminobenzylthio)imidazole in a mixture of 40 ml of chloroform and 10 ml of methanol was portionwise added under chilling with ice 880 mg (4.11 mmol, purity 80%) of m-chloroperbenzoic acid. The mixture was then stirred for 30 min. To the stirred mixture was added a saturated aqueous sodium hydrogencarbonate. The resulting aqueous solution was subjected to extraction with 50 ml of chloroform. The chloroform portion was taken out and the subjected to extraction with three portions of 10 ml of 0.1N aqueous NaOH and one portion of 20 ml of 0.1N aqueous NaOH to transfer a product into the aqueous fractions. The last three aqueous fractions were combined and made ammonia-alkaline by addition of 20% aqueous ammonium chloride to precipitate a crystalline product. The product was collected, washed sufficiently with water and dried under reduced pressure at room temperature to give 637 mg of the desired compound as a pale yellow crystalline product, yield 66%.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCOCC2)c2ccccc21

Procedure:
The product obtained from Example 20 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as a crystalline white solid, m.p. 168°-170° C. (hexanechloroform). High Res. Mass Spec. Calcd. for C22H25N3O4 : 396.1923 (M+H) . Found: 396. 1922.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.I[C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][OH:17].[CH:23](=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH3:24].[NH4+].[Cl-]>C1COCC1>[C:28]([S:26]([NH:25][CH:23]([C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][OH:17])[CH3:24])=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: OCc1cc(Cl)ccc1I
Reactant: CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(NS(=O)C(C)(C)C)c1ccc(Cl)cc1CO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of iPr2NH (0.31 mL, 2.24 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol). The solution was stirred for 15 min at −78° C. and added to it in one portion was 2-iodo-5-chlorobenzyl alcohol (0.5 g, 1.86 mmol). This solution was stirred for 30 min at −78° C. then was concentrated in vacuo and placed under high vacuum for 1 h. The residue, under nitrogen atmosphere, was dissolved in THF (20 mL), cooled to −78° C., and 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol) was added. This solution was stirred for 15 min at −78° C. and added drop wise was N-ethylidene-2-methyl-2-propanesulfinamide from the previous step (0.274 g, 1.86 mmol) dissolved in THF (5 mL). This solution was stirred for 30 min at −78° C. then was allowed to equilibrate to ambient temperature over 1 h. Saturated NH4Cl was added (3 mL), and the mixture was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography eluting with a methanol in dichloromethane gradient (1% to 3% MeOH in 0.5% increments). After concentration of desired fractions in vacuo, the separate isomers of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol were obtained as a yellow oils (isomer 1(less polar) 120 mg; HPLC RT=2.93 min, method A; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3, 7.38 ppm (s, 1H), 7.36 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (d, 1H), 4.82 ppm (m, 1H), 4.54 ppm (d, 1H), 4.3 ppm (br s, 1H), 3.94 ppm (d, 1H), 1.54 ppm (d, 3H), 1.2 ppm (s, 9H); isomer 2(more polar) 38 mg; HPLC RT=2.69 min; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3 7.4 ppm (d, 1H), 7.365 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (m, 1H), 4.78 ppm (dd, 1H), 4.64 ppm (dd, 1H), 3.67 ppm (br s, 1H), 3.65 ppm (d, 1H), 1.52 ppm (d, 3H), 1.18 ppm (s, 9H)).