Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([O:7][CH3:8])=[CH:5][S:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>C(Cl)Cl>[Br:1][C:2]1[C:6]([O:7][CH3:8])=[C:5]([S:10]([Cl:9])(=[O:12])=[O:11])[S:4][CH:3]=1
Reactant: COc1cscc1Br
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1c(Br)csc1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a stirred solution of 3-bromo-4-methoxythiophene (550 mg, 2.85 mmol), prepared in Step C above, in 30 mL of methylene chloride at −78° C. was added dropwise along the inside wall of the flask chlorosulfonic acid (0.48 mL, 7.21 mmol). The mixture was stirred at −78° C. for 10 nm, continued at room temperature for 1 h, and filtered through a 1-in silica gel pad, rinsing with methylene chloride. The filtrate was concentrated in vacuo to give 270 mg of 4-bromo-3-methoxy-2-thiophene sulfonylchloride (33%) as a light yellow oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=O)C.[OH-].[Na+].Cl>CO>[CH:23]([C:21]1[C:19]([NH2:20])=[N:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4])=[CH2:24]
Reactant: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)c(=O)nc1N
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine (111 mg, 3.29 mmol) in 5 ml of methanol was added 1N NaOH (0.32 ml, 0.32 mmol) at room temperature. After stirring for 1 hour, 1N HCl (ca.0.3 ml) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction (MEGA Bond Elute LRC, eluent: H2O~H2O: MeOH=1: 1, step gradient) to give 5'-deoxy-5-vinylcytidine (82 mg, 98%) as colorless solid:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[O:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9](=[O:10])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[OH:8]
Reactant: O=C1CCc2ccccc2O1
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)CCc1ccccc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (1.40 g) was added to 3,4-dihydrocoumarine (2.01 g) and stirred for 0.5 hour at 70° C., thereby yielding the entitled compound (3.60 g) as white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][CH:28]5[CH2:29][CH2:30][CH2:31][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 65%), MS (ISP) m/z=441.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and rac-2-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1.C(Br)(Br)[Br:28]>>[Br:28][C:2]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)c(C(F)(F)F)nc12
Reactant: BrC(Br)Br
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Br)c2nc1C(F)(F)F

Procedure:
The sub-titled compound was prepared from the product of example 37, step (a) (1.5 g) and bromoform (30 ml) using the method of Example 3, step (b).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH2:12]([NH:16][OH:17])[CH2:13][CH2:14][CH3:15]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:16]([CH2:12][CH2:13][CH2:14][CH3:15])[O-:17])[CH3:2]
Reactant: CCCCNO
Reactant: CCOc1ccccc1C=O
Product: CCCC[N+]([O-])=Cc1ccccc1OCC

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 2-ethoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 44.5% yield as a liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[CH2:4][O:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCCO)cc2)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](COc2ccc(CCCC=O)cc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-butan-1-ol (5.0 g, 17.8 mmol) in DCM (180 ml) is added Dess-Martin periodinane (7.56 g, 17.8 mmol). The yellowish solution is stirred at room temperature for 1 hour. The resultant yellow suspension is treated with 1 N NaOH solution (200 ml) and stirred at room temperature for 30 minutes. The organic phase is separated, dried (MgSO4) and concentrated to give 4-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-butyraldehyde as a clear oil; 1H NMR (CDCl3): 1.42, (3H, s), 1.48 (3H, s), 1.95 (2H, dt, J=7.6 and 14.2 Hz), 2.46 (2H, dt, J=1.5 and 7.3 Hz), 2.62 (2H, t, J=7.6 Hz), 3.90-3.96 (2H, m), 4.07 (1H, dd, J=5.2 and 9.3 Hz), 4.19 (1H, dd, J=6.4 and 8.1 Hz), 4.49 (1H, p, J=5.8 Hz), 6.86 (2H, d, J=9.4 Hz), 7.10 (2H, d, J=9.4 Hz), 9.77 (1H, t, J=1.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH3:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O>C1C=CC=CC=1>[CH2:6]([N:5]1[CH2:4][CH2:3][CH2:2][NH:1][CH:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[CH2:7][CH3:8]
Reactant: O=Cc1ccccn1
Reactant: CCCNCCCN
Solvent: c1ccccc1
Product: CCCN1CCCNC1c1ccccn1

Procedure:
To a stirred solution of 1,5-diazaoctane (16) (0.58 g, 0.005 mol) in dry benzene (20 mL) was added dropwise pyridine-2-carboxaldehyde (0.535 g, 0.005 mol) in dry benzene (10 mL). The resulting solution was refluxed for 2 hr using a Dean-Stark trap to remove water. Finally, the solvent was removed completely by distillation to give compound (17) in quantitative yield (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].O>CCOC(C)=O>[CH3:1][O:2][C:3]1([C:8]([NH2:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(C(=O)O)CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 1-methoxycyclopentanecarboxylic acid (0.9 g, 6.24 mmol) in EtOAc (30 mL) was treated with CDI (1.316 g, 8.12 mmol), stirred at RT for 0.5 h, treated with NH4OH (˜15M, 0.729 mL, ˜10.9 mmol) and stirred at RT overnight. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-methoxycyclopentanecarboxamide (900 mg, 101%). 1H NMR (400 MHz, CDCl3): δ 6.45 (br s, 1H), 5.42 (br s, 1H), 3.24 (s, 3H), 2.07-2.04 (m, 2H), 1.90-1.87 (m, 2H), 1.75-1.73 (m, 4H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[F:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH:54]=O.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:54][C:53]4[CH:56]=[CH:57][CH:58]=[C:51]([F:50])[CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.012 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (916 mg, Example 121), 3-fluorobenzaldehyde (474 mg) and acetic acid (229.4 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O to precipitate product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to produce additional precipitate. The mixture was filtered thru a celite pad. The collected solid was rinsed by water (35 mL×2). The solid was dissolved in EtOAc (50 mL) and then eluted from the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as light pink solid (675 mg; 60%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H), 7.25 (m, 3H), 7.06 (m, 3H), 6.90 (m, 1H), 6.64 (m, 3H), 5.03 (s, 1H), 4.50 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.91 (d, J=13.5 Hz, 1H), 3.70 (m, 1H), 3.18 (d, J=13.5 Hz, 1H), 3.02 (m, 2H), 2.60 (m, 5H), 2.01 (m, 3H), 1.72 (m, 3H), 1.26 (t, J=7.0 Hz, 3H), 1.05 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OCC)=[O:19].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:29]([CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[S:5][C:4]=1[CH2:18][OH:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccccc1

Procedure:
Prepared from intermediate 43 and phenol
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH3:14].[H-].[Na+]>CN(C)C=O>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)[CH3:14]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(O)c(C(C)(C)C)c1
Temperature: -78 °C
Yield: 22 %

Procedure:
A mixture of 19.85 g of tert-butylhydroquinone, 10.7 ml of ethyl bromide and 200 ml of dimethylformamide (DMF) was cooled to -78° C., and 4.82 g of 62.5% sodium hydride was added to the mixture. The temperature of the mixture was raised to 0° C., and the mixture was further stirred under ice-cooling for 30 minutes. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1), and recrystallized from hexane to give 5.045 g of 4-ethoxy-2-tert-butylphenol (yield: 22%, melting point: 96°-98° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N:17]=[C:18]=[S:19])[CH2:3][CH2:2]1.[NH3:20]>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([NH2:20])=[S:19])[CH2:5][CH2:6]1
Reactant: N
Reactant: FC(F)(F)c1ccc(N2CCOCC2)c(N=C=S)c1
Solvent: CCO
Product: NC(=S)Nc1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
Reaction of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with 33% ethanolic ammonia solution (50 ml) at room temperature for 2 hours gave 1-(2-morpholino-5-trifluoromethylphenyl)thiourea (m.p. 196°-197° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[N:19][S:18]2(=[O:45])=[O:44])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31])=[N:19][S:18]2(=[O:44])=[O:45])=[CH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Yield: 54.7 %

Procedure:
To a solution of [3-(4-{2-[(S)-3-(tert-Butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)prop-2-ynyl]carbamic acid tert-butyl ester (89 mg) in methanol (25 ml) was added palladium on charcoal (5%, 25 mg), and the solution was stirred in a hydrogen atmosphere for 1 h. The mixture was filtered and the filtrate was concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (49 mg) with a molecular weight of 678.0 g/mol (C34H52FN3O6SSi).
Reaction SMILES: C[C:2]1(C)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[C:7]([S:13][CH2:14][N+:15]([O-:17])=[O:16])[C:8]=2[CH3:12])O1.CC1C(SC#N)=C(C)C=C2C=1CCC[S:26]2>>[CH3:12][C:8]1[C:7]([S:13][CH2:14][N+:15]([O-:17])=[O:16])=[C:6]([CH3:18])[CH:5]=[C:4]2[C:9]=1[CH2:10][CH2:11][CH2:2][S:26]2
Reactant: Cc1cc2c(c(C)c1SC#N)CCCS2
Reactant: Cc1cc2c(c(C)c1SC[N+](=O)[O-])CCC(C)(C)O2
Product: Cc1cc2c(c(C)c1SC[N+](=O)[O-])CCCS2
Yield: 44 %

Procedure:
Using similar procedures to that described in parts (ii) and (iii) of Example 8, but starting from 5,7-dimethyl-6-thiocyanatothiachroman (J), 5,7-dimethyl-6-(nitromethylthio)thiachroman was obtained in 44% yield as a pale yellow gum which slowly solidified; NMR: 2.17(2H,m), 2.4(3H,s), 2.43(3H,s), 2.69(2H,t), 2.95(2H,m), 5.19(2H,s), 6.91(1H,s).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl.[CH3:20][C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:32])[CH2:22][NH:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1([CH3:32])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][CH2:22]1
Reactant: CC(C)(CNC(=O)c1ccccc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CN=C(c2ccccc2)c2ccccc21
Temperature: 150 °C
Yield: 54 %

Procedure:
1.42 g (10.0 mmol) of P2O5 and POCl3 (4 ml) were added to a solution of 1.27 g (5.0 mmol) of N-(2-methyl-2-phenylpropyl)benzamide in xylene (20 ml) and the mixture was heated at 150° C. for 3 h. After cooling to RT the mixture was concentrated to small volume under vacuum. The residue was made alkaline with a 20% aqueous NaOH solution. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 634 mg (2.7 mmol) of 4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cccc1CCN
Product: Cc1ccc(S(=O)(=O)NCCc2cccn2C)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-toluenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30](F)=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][OH:46]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30]([O:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2
Reactant: CN(C)CCO
Reactant: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5F)ccc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5OCCN(C)C)ccc4c3)c2cc1OC
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of N-[6-(6,7-dimethoxy-(4-quinolyloxy))(2-naphthyl)](2-fluoro-(3-pyridyl))carboxamide (Step a, 62 mg, 0.13 mmol) and K2CO3 (166 mg, 1.3 mmol) in dry NMP (5 mL, Aldrich) was added N,N-dimethylethanolamine (35 mg, 0.36 mmol, Aldrich) at RT. The reaction was stirred at 110° C. for 16 h. The mixture was cooled and diluted with 60 mL of EtOAc, then washed with water and brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by prep-HPLC to give title compound as a white solid. MS (ESI, pos. ion) m/z: 539 (M+1). Mass Calc'd for C31H30N4O5: 538.22.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[F:1][C:2]([F:22])([F:23])[CH:3]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)C(Nc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(Nc1ccccc1)C(F)(F)F
Yield: 13.4 %

Procedure:
A solution of compound 326 (2.16 g, 6.48 mmol) and sodium hydroxide (2.60 g, 64.8 mmol) in water (5.2 mL) and ethanol (26 mL) was stirred at room temperature for 24 h. The solvents were removed under reduced pressure leaving a white solid which was triturated in ether, isolated by filtration, rinsed with ether and dried under high vacuum. The white solid was dissolved in water (12 mL), and the solution was neutralized to pH 4 with a 3N HCl solution, extracted twice with EtOAc, the combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The solid was dissolved in dry toluene (20 mL), heated to reflux for 1 h with continuous stirring, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent EtOAc-hexane, gradient 0:100 to 40:60) to afford title compound 327 (204 mg, 0.87 mmol, 13% yield) as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.24-7.18 (m, 2H), 6.82 (tt, J=7.2, 1.0 Hz, 1H), 6.75-6.71 (m, 2H), 4.55-4.45 (m, 1H), 2.89 (dd, J=16.0, 4.4 Hz, 1H), 2.67 (dd, J=16.0, 8.8 Hz, 1H). LRMS (M−1) 231.9 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O)=O.C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: C=O
Solvent: O
Solvent: O=CO
Product: CN1CC[C@@H](c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 113.9 %

Procedure:
(S)-tert-Butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (456 mg, 1.12 mmol, Eq: 1.00) was dissolved in a mix of formic acid (20.0 ml) and formaldehyde, 37% (40 ml). The reaction mixture stirred at 70° C. for 18 h. The solution was cooled to room temperature and water was added. The aqueous solution was extracted once with DCM. The aqueous layer was Brought to pH=14 with solid K2CO3. A solid formed and was filtered to give (S)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (408 mg, quantitative yield). LC/MS-ESI observed [M+H]+ 320.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.ClCCl>C(O)C>[ClH:29].[Cl:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2cccc(Cl)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
1-(2-((2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic methyl ester (0.60 g, 0.0014 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.35 ml) was introduced. After stirring the solution at room temperature for 3 h, 37% hydro chloric acid solution was added, until the pH 1. Dichloromethane (200 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated twice with acetone. The residue was recrystallized from acetone/ethyl acetate to give the title compound (0.33 g, 55%) as white crystals.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CO.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:1])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 12.4 mmol) was added dropwise into a solution of 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylic acid (2.0 g, 8.3 mmol) in MeOH (20 mL) and toluene (20 mL) at 0° C. After 10 minutes at 0° C., the resulting mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.1 g, quantitative), used without further purification in the next step. HPLC (Method A) Rt 3.95 min (purity 95.5%). 1H NMR (CDCl3, 300 MHz) δ 8.23 (d, J=1.3 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.28-7.18 (m, 4H), 7.08 (d, J=7.3 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H), 3.92 (s, 3H), 2.01 (s, 3H), 1.61 (t, J=5.7 Hz, 1H).