Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[Cl:25])(=[O:4])=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[Cl:25])(=[O:3])=[O:4])(=[O:28])[CH3:27]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)c(Cl)c2)=C(c2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl

Procedure:
150 mg of 5-{4-(aminosulfonyl)-3-chlorophenyl}-2,2-dimethyl-4-phenyl-3(2furanone (Example 367) in 10 ml dichloromethane was reacted with 0.3 ml acetic anhydride in the presence of 0.5 ml triethylamine and 15 mg of 4-(N,N-dimethylamino)pyridine at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, which was followed by extraction with 30 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/ethylacetate 2:1) to afford 113 mg of 5-[4-{(acetylamino)sulfonyl}-3-chlorophenyl]-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 194-195° C. NMR: δ1.57 (s, 6H), 2.10 (s, 3H), 7.27 (m, 2H), 7.40 (m, 3H), 7.68 (dd, J=8.4, 1.8 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.45 (br s, 1H). IR (cm−1): 3195, 3104, 1698, 1377, 1164.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Yield: 59.4 %

Procedure:
A mixture of 3.0 g (13 mmol) 5-Bromo-6-chloro-nicotinic acid, 1.4 g (19 mmol) (hydroxymethyl)cyclopropane and 2.85 g (51 mmol) potassium hydroxide in DMSO (12 mL) was heated under microwave radiation for 6 min to 100° C. 50 mL water and 150 mL citric acid (10%) was added. A solid precipitated, was filtered off, re-dissolved in ethyl acetate and dried with Na2SO4. The product crystallized upon evaporation of the solvent from ethyl acetate/heptane 1:1 to yield 2.1 g (71%) of the title compound as white solid, MS (ISP): 270.3 (M−H).
Reaction SMILES: [CH3:1][N+:2]([O-:4])=[O:3].CO[Na].[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1>CCO>[CH3:8][N:9]1[CH2:14][CH2:13][C:12]([CH2:1][N+:2]([O-:4])=[O:3])([OH:15])[CH2:11][CH2:10]1
Reactant: CN1CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: CO[Na]
Solvent: CCO
Product: CN1CCC(O)(C[N+](=O)[O-])CC1
Yield: 40.2 %

Procedure:
CH3NO2 (6.6 mL, 122 mmol) and MeONa (221 mg, 4.1 mmol) was added to a solution of compound 1-methylpiperidin-4-one (10 mL, 81.3 mmol) in EtOH (10 mL). After 30 min more ethanol (15 mL) was added to facilitate stirring. The reaction mixture was stirred at room temperature for 2 days and then filtered through celite. The isolated solid was washed with ether to give the product 1-methyl-4-(nitromethyl)piperidin-4-ol (5.7 g, yield 40.4%). 1H-NMR (DMSO-d6/400 MHz): δ 5.01 (s, 1H), 4.47 (s, 2H), 2.41-2.40 (m, 2H), 2.21-2.15 (m, 2H), 2.12 (s, 3H), 1.64-1.53 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][NH2:13])=[CH:4][CH:3]=1.[C:14]([C:19]1[C:20](=[O:32])[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][C:24]=1[OH:25])(=O)[CH2:15][CH2:16][CH3:17]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1
Reactant: CCCC(=O)C1=C(O)CC(C2CCOCC2)CC1=O
Reactant: NOCCC#Cc1ccc(F)cc1
Solvent: CO
Product: CCCC(=NOCCC#Cc1ccc(F)cc1)C1=C(O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2.7 g (15 mmol) of 4-(4-fluorophenyl)-but-3-inoxyamine were added to a solution of 4 g (15 mmol) of 2-butryl-3-hydroxy-5-tetrahydropyran-4-yl-cyclohex-2-enone in 60 ml of dry methanol. After stirring for 16 hours at room temperature, the methanol was removed under reduced pressure from a water pump. The crude product was purified by means of chromatography over silica gel (mobile phase: methylene chloride). Yield 81.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:52]>>[ClH:52].[CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([OH:37])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3 hours. Petroleum ether (70 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.10 g of 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[C:33]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C@@H:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=1)[N:7]1[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]1[CH3:32])(=[O:35])[CH3:34]
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(C)=O)c2)C[C@H]1C
Yield: 70.3 %

Procedure:
A solution of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.2 g, 2.8 mmol, Example 6), acetic anhydride (0.40 mL, 4.2 mmol), and triethylamine (0.80 mL, 5.6 mmol) in 30 mL of dichloromethane was stirred overnight under nitrogen. The solution was washed twice with 15 mL of 5% sodium bicarbonate, dried over sodium sulfate and the solvent removed. The product was purified by chromatography on silica gel with ethyl acetate (30-100%) in dichloromethane to give 0.94 g (71%) of (±)-4-((αR*)-3-acetoxy-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a white foam. NMR (200 MHz, DMSO-d6): δ 0.9 (d, J=6 Hz, 3H); 1.1 (d, J=6 Hz, 3H); 1.0-1.2 (br m, 6H); 1.75 (dd, J1 =7.5 Hz, J2 =12 Hz, 1H); 2.1 (dd, J1 =8.5 Hz, J2 =12.5 Hz, 1H); 2.2 (s, 3H); 2.4-2.6 (m, 3H); 2.7 (m, 1H); 2.8 (dd, J1 =7.5 Hz, J2 =15 Hz, 1H); 3.1 (dd, J1 =6 Hz, J2 =14 Hz, 1H); 3.1-3.4 (br m, 4H); 5.05 (d, J=15 Hz, 1H); 5.1 (s, 1H); 5.15 (d, 10 Hz, 1H), 5.8 (m, 1H) 7.0 (s, 1H); 7.0 (d, J=8 Hz, 1H); 7.15 (d, J=8 Hz, 1H); 7.25 and 7.4 (ABq, J=8 Hz; 4H); 7.4(t, J=8 Hz, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. After the solvent was removed, the salt was dissolved in a minimal amount of dichloromethane and precipitated with diethyl ether. Filtration gave 0.50 g of the hygroscopic salt. Calc for C29H39N3O3HCl H2O: C, 65.46; H, 7.97; N, 7.90; Cl, 6.66. Found: C, 65.43; H, 7.97; N, 8.00; Cl, 6.79.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:19])=[N:6][CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[CH3:39][O:40][C:41](Cl)=[O:42]>C1COCC1.Cl>[CH3:39][O:40][C:41](=[O:42])[NH:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:6][CH:5]=1
Reactant: COc1cccc(C(=O)c2ncc([N+](=O)[O-])c3cc(OC)c(OC)cc23)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
The above [4-nitro-6,7-dimethoxy-isoquinolin-1-yl]-(3-methoxy-phenyl)-methanone (150 mg, 0.407 mmol) was treated with tin chloride (459 mg, 2.03 mmol) in THF (30 mL) and 6N HCl (19 mL) at room temperature overnight. The reaction mixture was treated with ice-cold saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and dried to a crude solid. 75 mg (0.203 mmol) of this crude solid was dissolved in dry THF (5 mL) and treated with pyridine (24.6 uL, 0.364 mmol) and methylchloroformate (18.7 uL, 0.243 mmol) under argon at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and evaporated to crude product. Preparative HPLC purification yielded 23 mg of [6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-carbamic acid methyl ester; trifluoro-acetic acid salt as an off-white solid: APCI-MS (M+H+) m/e calcd for C21H20N2O6 397.4, found 397.4; 1H NMR (300 MHz) compatible.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])=[N:6][CH:5]=1.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][C:7]([CH2:11][CH:12]([CH3:13])[CH3:14])=[C:8]([CH3:10])[CH:9]=3)[N:15]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:17]
Reactant: Cc1cc(C(=N)NO)cnc1CC(C)C
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Product: CCc1cc(-c2nc(-c3cnc(CC(C)C)c(C)c3)no2)cc(C)c1O

Procedure:
2-Ethyl-4-[3-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared from N-hydroxy-6-isobutyl-5-methyl-nicotinamidine and 3-ethyl-4-hydroxy-5-methyl-benzoic acid in analogy to Example 13, LC-MS: tR=1.02 min, [M+1]+=352.09.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:8][C:9]#[N:10])[CH2:5][C:6]#[N:7].S(OC)(O[CH3:15])(=O)=O>O1CCCC1>[CH3:15][O:3][CH:4]([CH2:8][C:9]#[N:10])[CH2:5][C:6]#[N:7]
Reactant: N#CCC(O)CC#N
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CC#N)CC#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Into a tetrahydrofuran solution, 0.7 g of sodium hydride was added. After cooling to 0° C., 3 g of 3-hydroxyglutaronitrile dissolved in a tetrahydrofuran solvent was slowly dropped. After completing the dropping, dimethyl sulfate was slowly added dropwise and stirred at 0° C. for 15 minutes. After stirring at room temperature for 6 hours, the reactant was extracted using water and dichloromethane and distilled under a reduced pressure to obtain 3-methoxy glutaronitrile (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:7]3[C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=5[O:9][CH:8]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4c(Cl)cccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4c(Cl)cccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(7-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (116) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Yield: 72 %

Procedure:
Obtained (2.43 g, yield 72%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (13.82 mmol, 3.0 g), 3-methoxyphenylboronic acid (13.82 mmol, 2.10 g).
Reaction SMILES: C([O:8][CH:9]1[CH2:12][C:11]2([CH2:16][C:15]([C:17]3[CH:22]=[N:21][C:20]4[N:23]([CH2:26][CH3:27])[N:24]=[CH:25][C:19]=4[C:18]=3[NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:14][O:13]2)[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH2:26]([N:23]1[C:20]2=[N:21][CH:22]=[C:17]([C:15]3[CH2:16][C:11]4([CH2:10][CH:9]([OH:8])[CH2:12]4)[O:13][N:14]=3)[C:18]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:19]2[CH:25]=[N:24]1)[CH3:27]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C3=NOC4(C3)CC(OCc3ccccc3)C4)cnc21
Agent: [Pd]
Solvent: CO
Product: CCn1ncc2c(NC3CCOCC3)c(C3=NOC4(C3)CC(O)C4)cnc21
Reaction time: 12 h
Yield: 39 %

Procedure:
Palladium/carbon (10%, 0.010 gm) was added to a solution of 5-[2-(benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.055 gm, 0.12 mmol) (example 34) in methanol and the reaction mixture was stirred under hydrogen balloon for about 12 hours. It was filtered through a bed of celite and residue was washed with methanol. The combined filtrate was concentrated under reduced pressure to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[Cl:20][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (4.8 g, 19.5 mmol), phosphorous oxychloride (7.2 mL, 78 mmol), and N,N-dimethylaniline (0.87 mL, 7.0 mmol) was stirred at 100° C. for 2 h. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4), and evaporated in vacuo. The remaining solid was crystallized from EtOAc to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (3.50 g, 66%) as a yellow solid; mp 151–153° C.
Reaction SMILES: [C:1]1([C:7]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OCCCCC(OC(C)(C)C)=O)=O)[CH2:14]3)[S:10](=[O:30])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>ClCCl>[C:31]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[S:10](=[O:30])[CH2:9][CH2:8]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCCCOC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Yield: 123.8 %

Procedure:
3.98 g of 4,4-diphenyl-6-tert-butyloxycarbonylbutyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the 1RS,4aSR,7aSR and 1RS,4aRS,7aRS isomers) are treated with 40 cm3 of a mixture of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 by volume) for 48 hours at 20° C. The solution is concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The oil obtained is taken up in 30 cm3 of dichloromethane, the solution is washed with 60 cm3 of a 2N aqueous solution of sodium hydroxide, the aqueous phase is extracted with 20 cm3 of dichloromethane. The organic extracts are pooled, dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is taken up in diisopropyl oxide and then concentrated to dryness at 40° C. under reduced pressure (2.7 and then 0.13 kPa). 3.0 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide are obtained in the form of a white meringue.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1nccs1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1nccs1)C2
Yield: 96 %

Procedure:
A mixture of 4-methyl-7-(2-thiazolyl)-5,6,7,8-tetrahydroquinolin-5-one (0.68 g), aminoguanidine hydrochloride (0.37 g), concentrated hydrochloric acid (0.7 ml), water (0.7 ml) and ethanol (25 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7-(2-thiazolyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 118) (0.9 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:11]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-sulfonyl)phenyl]-3(2H)-pyridazinone (Example 482, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:24][CH3:25])[CH2:9][N:10]([N:19]1[CH:23]=[N:22][N:21]=[CH:20]1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:8][CH2:9][N:10]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCCSc2ccc(O)cc2)n2cnnc2)cc1
Reaction time: 18 h

Procedure:
Potassium carbonate (500 mg) was added to a solution of 4-[(2-bromo-butyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03001, 384 mg, 1.2 mmol) and 4-hydroxythiophenol (227 mg, 1.8 mmol) in DMF (20 mL). The mixture was stiffed for 18 hours at r.t., diluted with ethyl acetate (100 mL) and extracted with water (two times 30 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.30). The resulting oil was dissolved in a small amount of ethyl acetate and the product was precipitated by addition of hexane. Yield: 289 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=1.48-1.64 (m, 4H) 2.81 (t, J=6.6 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0, 2H), 8.94 (s, 2H), 9.56 (s, 1H, —OH). LRMS (FAB+): 366.1 (100, [M+H]+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C(Cl)(Cl)Cl>[Pd].C(O)C>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1

Procedure:
4-((S)-2-Azido-1-phenyl-ethylamino)-quinazoline-8-carboxylic acid amide ((0.28 g, 0.84 mmol) and palladium on carbon (5%, wet type, 56 mg) were combined in ethanol (5 mL) and chloroform (1 mL) and stirred under an atmosphere of hydrogen for 48 hours. The solution was filtered, rinsed with methanol and the solvent removed under reduced pressure. The sample was redissolved in THF/methanol and hydrogen chloride (4M solution in dioxane, 1 mL) was added. The solid formed was collected by filtration and purified by recrystallization from methanol/ethyl acetate (131 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27-3.40 (m, 1 H) 3.84-3.98 (m, 1 H) 5.99 (br. s., 1 H) 7.29-7.36 (m, 1 H) 7.39 (t, J=7.39 Hz, 2 H) 7.60 (d, J=7.32 Hz, 2 H) 7.88 (s, 1 H) 8.16 (br. s., 1 H) 8.43 (br. s., 3 H) 8.59 (d, J=0.83 Hz, 1 H) 8.80 (s, 1 H) 9.29 (br. s., 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27](Cl)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH2:38]([NH2:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([NH:43][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)NCC(C)(C)C)c1
Reaction time: 6 h

Procedure:
A solution of the title E compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-benzenesulfonyl chloride (1.12 g, 2.5 mmol) in 20 mL of CH2Cl2 is treated sequentially with N-methylmorpholine (NMM; 550 mL, 5 mmol) and neopentylamine (442 mL, 3.75 mmol) at RT. After 6 h, the mixture is partitioned between water and EtOAc, and the organic solution is washed with aqueous 1N HCl and brine, dried over anhydrous Na2SO4 and concentrated to afford 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-N-(2,2-dimethylpropyl)benzenesulfonamide: NMR (CDCl3) 0.78 (s, 9H), 2.22 (s, 6H), 2.58 (d, 2H, J=7.5), 4.82 (t, 1H, J =7.5), 5.18 (s, 2H), 6.88 (dd, 1H, J=9, 3.7), 7.03 (d, 1H, J=9), 7.33-7.51 (m, 6H), 8.04 (s, 2H).