Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 78.2 %

Procedure:
To a round bottom flask was added azepan-4-ol (300 mg, 2.60 mmol), 1-fluoro-4-nitrobenzene (368 mg, 2.60 mmol), Cs2CO3 (1018 mg, 3.13 mmol) and DMF (5 mL). The reaction was stirred at 100° C. for 10 hrs. The reaction was diluted with EtOAc (50 ml), washed with water (4×20 ml) and saturated aqueous NaCl (25 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/He) to give the product, 1-(4-nitrophenyl)azepan-4-ol (480 mg, 2.032 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C12H16N2O3 m/z 236.2, found: 237.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.18-8.03 (m, 2H), 6.71-6.57 (m, 2H), 4.00 (br. s., 1H), 3.74-3.60 (m, 1H), 3.60-3.41 (m, 3H), 2.22-2.01 (m, 2H), 1.95-1.72 (m, 4H); 13C NMR (101 MHz, CDCl3) δ ppm 153.41, 136.89, 126.38, 110.02, 69.88, 49.24, 44.00, 35.87, 34.96, 21.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[Cl:24]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
Following the procedure outlined in Example 4, 5.00 g (17.1 mmol) of (2-chlorophenyl) diphenyl methanol, designated as T-3 on Appendix A, was treated with 2.5 ml thionyl chloride (34 mmol) according to general method B to give 4.39 g (82%) of (2-Chlorophenyl) diphenyl chloromethane, mp: 131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(F)cc1F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(F)cc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (2,4-difluorophenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 525 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=1>>[NH2:15][C:13]1[N:12]=[C:11]([NH:16][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:10]=[C:9]([Cl:8])[N:14]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 80 °C

Procedure:
8.6 cm3 butylisocyanate was added to a suspension of 5 g 6-chloro-2,4-diaminopyrimidine in 50 cm3DMSO. The reaction medium was maintained at 80° C. until it was shown by TLC that the starting compound had disappeared.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C@@H:14]1[C@H:19]2[CH2:20][C@@:16]([N:21]=[S:22](=[O:24])=[O:23])([CH2:17][CH2:18]2)[C@@H:15]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].[OH-].[K+].Cl>CO.O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C@@H:14]1[C@H:19]2[CH2:20][C@@:16]([N:21]=[S:22](=[O:24])=[O:23])([CH2:17][CH2:18]2)[C@@H:15]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H](c2ccc3oc4ccccc4c3c2)[C@@H]2CC[C@]1(N=S(=O)=O)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC/C=C\C[C@@H]1[C@H](c2ccc3oc4ccccc4c3c2)[C@@H]2CC[C@]1(N=S(=O)=O)C2
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Methyl (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)-sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (234 mg, 0.50 mmol) was dissolved in methanol (6 ml)/tetrahydrofuran (4 ml). To the solution was added 1 N potassium hydroxide (1.50 ml, 1.50 mmol) under ice-cooling. After the reaction mixture was warmed up to room temperature, it was allowed to react for 16 hr and concentrated to remove the solvent. To the residue were added ethyl acetate (50 ml) and water (10 ml), and then 1 N HCl (2.00 ml, 2.00 mmol), and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:1) containing 0.2% acetic acid) to yield (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)-sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1a-2) (203 mg, 0.434 mmol). Yield 87%, oil.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]([N:24]3[CH2:30][C:29]4[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:28]=4[O:27][CH2:26][CH2:25]3)[C:16]=2[CH2:15]1>>[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]([N:24]3[CH2:30][C:29]4[CH:31]=[C:32]([C:2]5[CH:11]=[N:10][C:9]6[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=6[CH:3]=5)[CH:33]=[CH:34][C:28]=4[O:27][CH2:26][CH2:25]3)[C:16]=2[CH2:15]1
Reactant: O=C1COc2cc(Br)cnc2N1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6c(c5)OCC(=O)N6)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 7-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 8.38 (s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 7.07 (d, 1H), 4.68 (s, 2H), 4.62 (s, 2H), 4.33 (m, 2H), 3.82 (m, 2H), 2.71 (t, 2H), 2.45 (s, 2H), 1.56 (t, 2H), 0.84 (s, 6H); MS (EI) for C26H27N5O3: 458 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][S:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mol) was combined with methanesulfonyl chloride (0.043 mL, 0.56 mol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give tert-butyl 4-[(methylsulfonyl)amino]piperidine-1-carboxylate, LCMS [M+Na]+: m/z=301.0. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired HCl salt, which was used directly in the next step. LCMS calculated for C6H15N2O2S (M+H)+: m/z=179.1; Found: 179.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[C:22]([CH3:29])([CH3:28])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 41.5 %

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (18.0 g) in N,N-dimethylformamide (70 ml) were added potassium carbonate (25.1 g) and ethyl 2-bromoisobutyrate (20.0 g), and the mixture was heated at 80° C. with stirring. Ten hours later, the reaction solution was cooled to 25° C., and water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (11.8 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]#[N:21])[CH2:16]1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][C@@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]#[N:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CC[C@@H](N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, ((1R,3R)-3-cyano-cyclopentyl)-carbamic acid tert-butyl ester (crude from Step 2) was dissolved in dichloromethane (2.5 ml). The solution was cooled to 0° C. and trifluoroacetic acid (1.1 ml, 14.3 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h then concentrated to give (1R,3R)-3-amino-cyclopentanecarbonitrile trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:20]=[CH:19][N:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc(NC3=NN(c4ccccc4)CC3)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: c1ccc(COc2ccc(Nc3ccn(-c4ccccc4)n3)cc2)cc1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
Manganese dioxide (2.5 g) was added portionwise over 10-15 minutes to a solution of the product of step (a) (3.43 g) in dichloromethane (300 ml) stirred at room temperature. After stirring for an additional 30 minutes at room temperature, the reaction mixture was filtered, solvent was removed and the resulting gum was chromatographed on silica gel eluting with dichloromethane: ethyl acetate (95:5) to give the title compound (2.45 g) mp 145°-146°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[CH2:18].[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([CH3:13])[CH:15]=3)[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: C=Cc1cccc(C)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: Cc1cccc(CCN2CCN(c3ccccc3)CC2)c1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.30 ml) of 3-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-[2-(3-methylphenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[C:32]([O-])([O-])=[O:33].[K+].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)([CH2:32][OH:33])[CH2:10][OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol) and p-toluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95° C. for 1 h. The solution was washed with aq NaHCO3 (10 mL) and water (20 mL). The organic layer was dried and concentrated. The residue was dissolved in EtOH (20 mL). To the solution was added formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) and K2CO3 (1.44 g, 10.45 mmol). The mixture was stirred at 85° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL×4). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether˜Petroleum ether: EtOAc=2:1) to afford 4.6 g of 2,2-bis(3-bromophenyl)propane-1,3-diol (11.9 mmol, 57% after two steps). LC/MS: [M−18+1]=368. 1HNMR (CDCl3), 400 MHz: δ 2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[CH:17][CH:16]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)#[N:2].[OH-].[Na+].CC[OH:30].OO>CS(C)=O.O>[CH3:22][N:21]([CH3:23])[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:4]2[C:3]([C:1]([NH2:2])=[O:30])=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:25][CH:24]=1)=[O:20]
Reactant: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
4-[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]-N,N-dimethylbenzamide (83 mg, 0.250 mmol) and 5 N sodium hydroxide (0.351 mL, 1.753 mmol) were taken up in DMSO (1 mL)/EtOH (1 mL) and warmed to 60° C. Hydrogen peroxide (0.329 mL, 3.76 mmol) was added dropwise and stirring continued at 60° C. for 15 minutes. Room temperature was attained, water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine (×2), dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (25-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc followed by 15% MeOH—CHCl3) gave 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17][CH2:18][CH2:19]CC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:17][CH2:18][CH3:19])#[N:2]
Reactant: CCCCCBr
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: CCCCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromopentane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[K].CCO[C:14](S)=[S:15].C(OCC)C>C(O)C>[SH:15][C:14]1[NH:1][C:2]2[C:3](=[O:9])[NH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CCOC(=S)S
Reactant: Nc1ccnc(O)c1N
Agent: [K]
Solvent: CCO
Solvent: CCOCC
Product: O=c1[nH]ccc2nc(S)[nH]c12
Temperature: 25 °C

Procedure:
A suspension of 5.0 g (39.96 mmol) of 3,4-diamino-2-hydroxypyridine and 12.82 g (80.0 mmol) of potassium-ethyl xanthogenate in 100 ml of ethanol was refluxed for three hours. The mixture was then cooled to ambient temperature and combined with approx. 20 ml of diethyl ether. The precipitated product was filtered off, washed with approx. 10 ml of diethyl ether, dried, dissolved in approx. 30 ml of water and this solution was acidified with concentrated hydrochloric acid. The product precipitated was suction filtered, washed with 15 ml of water and dried at 50° C.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:13]([N:15]1[CH2:29][CH2:28][CH2:27][C@H:16]1[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[NH:1]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:2]([C:13]([N:15]1[CH2:29][CH2:28][CH2:27][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Substance [5] (52.78 g, 106.29 mM) was dissolved in methanol (300 ml). 1 N NaOH (150 ml, 1.4 molar excess) was added dropwise during 20 minutes with ice cooling and then the mixture was stirred at room temperature. 1 N HCl (43.71 ml, 0.4 molar excess) was added with ice cooling to adjust to pH 7 and methanol was distilled off in vacuo. The aqueous layer was washed with ether (150 ml) and the pH of the aqueous layer was adjusted to pH 3 by adding 1 N HCl (110 ml). The solution was extracted twice with ethyl acetate (300 ml and 150 ml). The extract was dried by adding anhydrous sodium sulfate, then concentrated in vacuo. Ether and hexane were added to the residue to obtain the precipitate. The same operation was repeated and the precipitate was dissolved in ethyl acetate, then dried in vacuo to obtain the foaming solid substance [6] (32.27 g, yield: 77.75%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH:34]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:34][C:33]3[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy)-8-acetyl-3-methylflavone (2.61 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 82-84° C., 1H-NMR (CDCl3) δ:1.76 (s, 3H); 2.20 (s, 3H); 3.82 (s, 3H); 4.62 (s, 2H); 5.05 (d, 2H, J=18 Hz); 6.95-7.10 (m, 3H); 7.09 (d, 1H); 7.10 (d, 1H, J=9 Hz); 7.31 (d, 1H, J=16 Hz); 7.40-7.45 (m, 3H); 7.55-7.58 (m, 2H); 7.31 (s, 2H); 8.32 (d, 1H, J=8.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:24]([O:26]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:30][NH:31][C:24](=[O:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccs1)C(c1ccc(F)cc1)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(F)cc1)C2c1nccs1
Temperature: 45 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (180 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the title compound (3 mg, yield: 2%). 1H-NMR (400 MHz, CD3O) δ (ppm): 4.88 (d, J=8.0 Hz, 1H), 5.09 (d, J=8.0 Hz, 1H), 7.01 (t, 2H), 7.21 (d, 1H), 7.36-7.40 (m, 2H), 7.47 (d, 1H), 7.59 (d, 1H), 7.65 (t, 1H), 7.74 (d, 1H); 19F-NMR (400 MHz, CD3OD) δ(ppm): −116.36 (s); LC-MS (ESI) m/z: 365 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1CCO[CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.C(O)C.[ClH:44]>ClCCl>[ClH:44].[CH:24]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1)=[O:23]
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.2 g, 4.04 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (1.0 g, 4.04 mmol). Ethanol (10 mL) and dichloromethane (10 mL) were added to form a slurry. The reaction mixture was heated at 45° C. to 50° C. for about 18 hours and then cooled to room temperature. Aqueous 1M hydrochloric acid (10 mL) was added and the resulting mixture was stirred vigorously for about 3 hours. Dichloromethane (10 mL) was added and the resulting mixture was stirred for about 5 minutes. The layers were then separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to provide crude biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester hydrochloride (1.9 g). 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.4 (m, 2H), 1.58-1.75 (m, 2H), 2.0-2.17 (m, 2H), 2.19 (s, 3H), 2.38 (s, 3H), 2.41-2.50 (m, 4H), 2.5-2.75 (m, 2H), 4.31-4.42 (m, 1H), 7.10-7.35 (m, 9H), 7.55 (s, 1H), 7.75 (s, 1H), 8.59 (s, 1H), 9.82 (s, 1H), 9.98 (s, 1H); MS [M+H+] found 500.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:17](OC)[CH2:18][Br:19].N>S(=O)(=O)(O)O>[Br:19][CH2:18][CH:17]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: Nc1ncccc1Cc1ccccc1
Reactant: COC(CBr)OC
Agent: N
Agent: O=S(=O)(O)O
Product: BrCC1Nc2ncccc2Cc2ccccc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A mixture of 2-amino-3-benzylpyridine (12.0 g, 65.2 mmol) and bromoacetaldehyde dimethyl acetal (19 g, 112.4 mmol, 1.7 eq.) in a 250 ml round-bottomed flask was treated at room temperature with concentrated sulphuric acid (50 ml) by quick addition. A vigorous exothermic reaction took place. After stirring for one hour the dark mixture was poured on ice (ca. 500 ml). Concentrated ammonia was added to basify the mixture. Extraction was done with ethyl acetate (100 ml) and dichloromethane (2×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave 10-bromomethyl-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine as a brown powder (14 g, 48.6 mmol) in 75% yield. Mass analysis: M+1 289,291 (Br-isotope) major peak.