Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([CH3:17])[CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH:10]([CH3:17])[CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)C(C)CSc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CC(C)CSc1ccc(F)cc1
Yield: 96.8 %

Procedure:
1.00 Gram of 6-(4-fluorophenylthio)-4-hydroxy-5-methyl-2-hexanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 1.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.08 g of 6-(4-fluorophenylthio)-5-methyl-3-hexen-2-one. (trans : cis =3.7 : 1) (purity: 83.5%). The yield was 96.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=1)=[O:4]>O1CCCC1.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccc(CC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane-tetrahydrofuran complex (40 ml of a 1.0 molar solution in tetrahydrofuran) was added, dropwise over 10 minutes, to a solution of 4-(methoxycarbonylmethyl)phenylacetic acid (see U.S. Pat. No. 3,341,531) (7.7 g) in tetrahydrofuran (100 ml) at 0°. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of 2M hydrochloric acid (50 ml) then concentrated in vacuo. The residue was partitioned between dichloromethane (200 ml) and 2M hydrochloric acid (100 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 ml) and the solution extracted with saturated aqueous sodium bicarbonate (2×100 ml). The aqueous extracts were combined, acidified with 2M hydrochloric acid (pH5) and extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4 ) and concentrated in vacuo to give the title compound as an oil, yield 2.7 g.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1)=[O:5]
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid (Example 26b) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 203° C. (isopropanol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11](Br)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1.[C:26]([O-])([O-])=O.[Na+].[Na+].CB(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(C)cc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To the mixture of methyl(5-bromo-6-((2,4-dichlorobenzyl)oxy)-1-benzofuran-3-yl)acetate (166 mg), aqueous 2M Na2CO3 (0.561 mL) and methylboronic acid (44.7 mg) in DME (3.7 mL) was added Pd(Ph3P)4 (43.2 mg). The mixture was stirred at 80° C. for 7 h. To the mixture was added methylboronic acid (44.8 mg) again. The mixture was stirred at 80° C. under nitrogen atmosphere over weekend. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (45.0 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][C:21]1[N:22]=[CH:23][C:18]([Br:17])=[CH:19][N:20]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(Br)cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
3,5-Bis-trifluoromethyl-benzylamine (10 g) and 5-bromo-2-chloro-pyrimidine (12 g) are dissolved in 1,4-dioxane (50 ml) and thereto is added N,N-diisopropylethylamine (10.7 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (10.1 g). MS (m/z): 713 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]([O:16]CC)=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:20].CO>>[CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]([NH2:20])=[O:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OCC)nn1C(C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1cc(C(N)=O)nn1C(C)(C)C
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
Ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate (60 g, 0.24 mol) in a 1:1 mixture of concentrated ammonium hydroxide/methanol (238 mL) was heated at 125° C. for 37 hours in a pressure vessel. After cooling to ambient temperature, the vessel was placed in an ice bath. The reaction mixture was stirred for 30 minutes, then was concentrated under reduced pressure to a brown oil. The oil was dissolved in dichloromethane and the solution was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a wet brown solid. Hexanes were added, the mixture was stirred, and 18.67 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamide was isolated by filtration as an off-white solid.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=O)[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=12.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)[CH:7]=[CH:6][C:5]=12
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2nsnc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2nsnc2c1
Yield: 9.5 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzo[c][1,2,5]thiadiazol-5-yl)propan-1-one (552 mg, 2 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (384 mg, 2 mmol) to give the desired product (83 mg, 10%, Z/E=1/1).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:48]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:47]1[CH:48]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([B:25]([OH:27])[OH:26])=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:50]=[CH:51][CH:52]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Yield: 70 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 34D (800 mg, 1.37 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 34E (530 mg, 70%) as an oily brown solid. 1H NMR (400 MHz, MeOD) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 2.36 (s, 3 H) 2.67-2.85 (m, 2 H) 3.01 (t, J=7.07 Hz, 2 H) 4.06 (q, J=7.16 Hz, 2 H) 4.31 (t, J=7.07 Hz, 2 H) 4.96-5.11 (m, J=12.55, 12.55, 12.55 Hz, 3 H) 6.99 (d, J=7.33 Hz, 1 H) 7.15-7.25 (m, J=7.83, 7.83 Hz, 3 H) 7.31 (s, H) 7.35-7.43 (m, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([Cl:9])[NH:4][C:3]1=[O:10].Br[CH2:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:9][C:5]1[N:4]([CH2:12][C:13]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[C:3](=[O:10])[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2-Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for C13H9ClFN3O2, 293.68; found 293.68.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[NH2:18].[OH-].[Li+]>O.CO>[NH2:18][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(CN2CCN(C)CC2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(N)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid methyl ester (4.30 g, 10.0 mmol) in water (30 mL) and methanol (10 mL) was added lithium hydroxide (1.26 g, 30.0 mmol); the mixture was stirred at room temperature for 12 hours. An additional amount of lithium hydroxide (0.6 g, 15.0 mmol) was added, and heated at 40° C. for 15 hours; TLC indicated completion of the reaction. The mixture was cooled, concentrated, the residue was adjusted to pH ˜5 with 6 N HCl, and evaporated to dryness, to provide crude 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid. Yield: 6.2 g, along with inorganic salt. It was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.[NH2:14][CH:15]1[CH2:19][CH:18]([CH2:20][OH:21])[CH:17]([OH:22])[CH:16]1[OH:23].C(N(CC)CC)C>C(O)CCC>[NH2:8][C:7]1[C:2]([NH:14][CH:15]2[CH2:19][CH:18]([CH2:20][OH:21])[CH:17]([OH:22])[CH:16]2[OH:23])=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: NC1CC(CO)C(O)C1O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCSc1nc(Cl)c(N)c(NC2CC(CO)C(O)C2O)n1

Procedure:
The product of step iv) (4.6 g) was added to a solution of 3-amino-5-(hydroxymethyl)-cyclopentane-1,2-diol (1.41 g) in butan-1-ol (200 ml) containing triethylamine (10 ml) and the whole heated to reflux for 48 hours. Evaporation gave a dark residue which was chromatographed (SiO2, 10% ethanol/dichloromethane) to afford the sub-title compound (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)CC1

Procedure:
Intermediate 1 was coupled with 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH2:17]([NH2:19])[CH3:18].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1>[CH2:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1)[CH3:18]
Reactant: CCN
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCNc1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Yield: 91 %

Procedure:
To a solution of 6-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (1.0 g, 4.24 mmol) in dioxane (10 mL) was added ethylamine (3.58 mL, 70% in water) and the mixture was heated at 160° C. under microwave irradiation for 45 min. After cooling to RT, the mixture was poured into a mixture of THF:1 N HCl aq. solution=1:1 (25 mL) and stirred for 25 min at RT. The mixture was brought to pH=7 with a saturated aq. solution of NaHCO3 and extracted with CH2Cl2 (50 mL). The organic layer was washed with H2O (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to give 6-(ethylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde RBO 35180 as a yellow solid (941 mg, 91% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@:9]2([NH:18][C:19]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:20])[C@H:14]([CH2:15]O)[CH2:13][C@H:12]([CH3:17])[O:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].ClC1C=CC(C#N)=CC=1[C@]12CO[C@@H](C)C[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2>>[C:1]([C:3]1[CH:4]=[C:5]([C@:9]23[CH2:10][O:11][C@@H:12]([CH3:17])[CH2:13][C@H:14]2[CH2:15][S:20][C:19]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:18]3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2cccc(C#N)c2)CO1
Agent: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(C#N)ccc2Cl)CO1
Product: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(C#N)c2)CO1

Procedure:
N-{[(3S,4R,6S)-3-(3-Cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C23) was converted to the product using the method described for the synthesis of N-[(4aR,6S,8aS)-8a-(2-chloro-5-cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) in Example 6. The resulting product was used in the next step without further purification. Yield: 45.0 mg, 0.115 mmol, 40%. LCMS m/z 392.2 [M+H+].
Reaction SMILES: [C:1](=O)([O-])[O-].CI.[CH2:7]([N:14]1[C:26]2[C:25]([OH:27])=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[C:22]([CH3:33])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:7]([N:14]1[C:26]2[C:25]([O:27][CH3:1])=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[C:22]([CH3:33])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1cc(C)c2c3ccccc3n(Cc3ccccc3)c2c1O
Reactant: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)Cc1cc(C)c2c3ccccc3n(Cc3ccccc3)c2c1OC
Reaction time: 1 h
Yield: 101.1 %

Procedure:
120 mg of anhydrous pottasium carbonate and 0.14 ml of methyl iodide were added to 4 ml of a solution of 80 mg of methyl (9-benzyl-1-hydroxy-4-methylcarbazol-2-yl)acetate, as obtained in Example 219, in dimethyl formamide, at room temperature, and the reaction mixture was stirred for 1 hour. After this time, the reaction mixture was diluted with an excess of ethyl acetate, and then washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 15-20% v/v solution of ethyl acetate in hexane) to yield 84 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])\[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1Cl
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccccc1Cl
Temperature: 85 °C

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (m, 2H), 7.35 (m, 2H), 7.20 (m, 3H), 6.50 (s, 1H), 3.90 (m, 2H), 3.50 (m, 1H), 3.35 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.0 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][CH2:11][CH2:12][C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1>>[Cl:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:19]2[CH2:20][CH2:21][CH:16]([C@H:14]3[CH2:15][C@H:13]3[CH2:12][CH2:11][OH:10])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: Cc1nc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Product: Cc1nc(N2CCC([C@H]3C[C@H]3CCO)CC2)ncc1Cl

Procedure:
The titled compound was prepared from 2,5-dichloro-4-methylpyrimidine from step 1 of this example and rac cis-tert-Butyl 4-[-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to Example 6, step 2.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:12])[O:10]C(C)(C)[O:8][C:7]1=[O:15].[OH-].[Na+]>O1CCOCC1.O>[C:27]1([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH2:18][CH2:17][CH2:16][C:6]([C:11]([OH:12])=[O:10])([C:7]([OH:15])=[O:8])[CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CCC1(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)(C(=O)O)C(=O)O
Temperature: 100 °C

Procedure:
2.56 mmol of 2,2-dimethyl-4,6-dioxo-5-[3-[(triphenylmethyl)thio]propyl]-1,3-dioxane-5-propanoic acid methyl ester (II) (1.4 g) with 18 mmol of sodium hydroxide (0.72 g) was dissolved in a mixture of 5 ml of 1,4-dioxane and 5 ml of water. The mixture was then heated to 100° C. for 1 hour, evaporated to dryness, dissolved in water and precipitated by addition of 1 M sulfuric acid. The precipitate was filtered off, washed with water and dried in a dessicator. Yield 1.36 g of 6-[(triphenylmethyl)-thio ]-1,3,3-hexanetricarboxylic acid (III) (−100%), 13C-NMR (MeOH) δ 25.4, 29.2, 30.7, 33.5, 33.7, 58.0, 68.3, 128.1, 129.3, 131.2, 146.7, 174.9, 176.9.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[S:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 7-hydroxy-2,4-diphenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (93 mg, 0.25 mmole) and glycine (372 mg, 4.95 mmole) in 0.5 M sodium methoxide/methanol (9.4 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (50 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (7 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (79 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.28 (br s, 1H), 9.42 (t, 1H, J=6.2 Hz), 8.16 (m, 4H), 7.62 (m, 6H), 4.07 (d, 2H, J=5.8 Hz); MS: (+) m/z 406.27 (M+1).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH2:29].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH:29][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCCc2cccs2)nc1

Procedure:
Using a method similar to Example 1, using 6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 546 mg, 2.00 mmol), 2-thiopheneethylamine (305 mg, 2.40 mmol), Ti(iPrO)4 (1.14 g, 4.00 mmol), TiCl4 (1.0M/DCM, 4.00 ml, 4.00 mmol), and NaBH3CN (251 mg, 4.00 mmol) gives the title compound (491.mg) as a light yellow solid. Mass spectrum (ion spray): m/z=394 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 6.95-6.89 (m, 3H), 6.85 (m, 2H), 5.87 (br. s, 2H), 3.81 (t, 1H), 3.12-3.02 (m, 3H), 2.98 (m, 1H), 2.83-2.68 (m, 2H), 1.98-1.82 (m, 3H), 1.73 (m, 1H).