Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.Cl>CCOCC>[CH3:18][C:5]([CH3:17])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][OH:3]
Reactant: CCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCC(O)CCCCCC(C)(C)CO
Yield: 810.8 %

Procedure:
A solution of 2,2-dimethyl-8-oxododecanoic acid ethyl ester (14.33 g, 5.3 mmol) in Et2O (30 mL) was added to a suspension of LiAlH4 (4.6 g, 12 mmol) in Et2O (200 mL). The reaction mixture was heated to reflux for 2 h. Water (100 mL) and aqueous HCl (10%, 200 mL) were added. The aqueous solution was separated and extracted with Et2O (2×100 mL). The combined organic solutions were washed with saturated, aqueous NaHCO3 solution (100 mL) and brine (50 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexanes=1:10, 200 mL, then 1:3, 150 mL) to yield 2,2-dimethyldodecan-1,8-diol (9.9 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.55 (br s, 1H), 3.29 (s, 2H), 1.7 (br. s, 2H), 1.42-1.20 (m, 16H), 0.89 (t, J=7.2 Hz, 3H), 0.84 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 72.1, 72.0, 38.7, 37.6, 37.3, 35.2, 30.8, 28.0, 25.8, 24.0, 23.9, 22.9, 14.3. HRMS (LSIMS, gly): Calcd for C14H31O2 (MH+): 231.2324. found: 231.2324. HPLC: 99.8% pure. Elemental analysis (C14H30O2): Calcd for C, 72.99; H, 13.12. Found: C, 72.75; H, 13.23.
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([NH:19]C(OCC2C=CC=CC=2)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>[H][H].[Pd]>[ClH:1].[ClH:1].[NH2:19][CH:13]([CH2:12][CH2:11][CH2:10][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[NH:2])[NH:9]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[ClH:1]
Reactant: CCOC(=O)C(CCCC1CCCCC(=N)N1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C(N)CCCC1CCCCC(=N)N1

Procedure:
The product of EXAMPLE 249 is reduced using hydrogen and Pd/C as catalyst to yield the title product after lyophilization from aqueous HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Clc1ncccn1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ncccn1

Procedure:
The title compound, MS: m/e=296.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-pyrimidine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:16][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[N:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cn1
Reaction time: 4 h
Yield: 82.4 %

Procedure:
Benzyl bromide (1.367 ml, 11.49 mmol) was added to a solution containing 6-bromopyridin-3-ol (2 g, 11.49 mmol) and Potassium carbonate (2.383 g, 17.24 mmol) in Acetone (Volume: 38.3 ml). Let the reaction stir for 4 hours. Concentrated and purified by Combiflash using 15% ethyl acetate in hexanes to afford 5-(benzyloxy)-2-bromopyridine (2.5 g, 9.47 mmol, 82% yield).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC1C=CC(N2CCNCC2)=CC=1.[CH:29]1([CH2:32][CH2:33][NH:34][C:35]([C:37]2[N:38]=[N:39][C:40](Cl)=[CH:41][CH:42]=2)=[O:36])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][CH2:33][NH:34][C:35]([C:37]2[N:38]=[N:39][C:40]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[S:9][N:8]=4)[CH2:2][CH2:3]3)=[CH:41][CH:42]=2)=[O:36])[CH2:31][CH2:30]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nsc4ccccc34)CC2)nn1
Yield: 25 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 3-piperazin-1-ylbenzo[d]isothiazole to replace 1-(4-fluorophenyl)-piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 25% yield (0.0307 g). 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.94 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 4.05 (m, 4H), 3.73 (m, 4H), 3.51 (m, 2H), 1.50 (m, 2H), 0.73 (m, 1H), 0.45 (m, 2H), 0.06 (m, 2H). MS (ES+) m/z 409 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>C(N(CC)CC)C>[C:9]1([S:15]([C:5]2[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1n[nH]c(S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 4.8 g. of benzenesulfonyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 17.5 hours. The heterogeneous mixture is filtered and the colorless solid washed successively with ether, cold water and ether again, then air dried for approximately 10 minutes and dried in vacuo for 6 hours. The dried product is extracted with about 50 ml. of hot, dry acetonitrile then concentrated to about 25 ml. by water pump evacuation. The mixture is heated to redissolve the colorless crystalline solids which is again separated on cooling to room temperature. The solid is collected and washed with acetonitrile then dried in vacuo overnight, m.p. 150° -153° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([OH:12])[CH:11]=1)(=[O:3])[CH3:2].[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@@H:27]1OC(=N)C(Cl)(Cl)Cl)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@H:27]1[O:12][C:10]1[CH:11]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][C:9]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2ccc(COC(C)=O)cc2O)cc1
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(COC(C)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 5-acetoxymethyl-2-(4-ethylbenzyl)phenol (0.59 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (1.1 g) in dichloromethane (15 mL) was added boron trifluoride diethyl ether complex (0.31 mL), and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-3/2) to give 5-acetoxymethyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1.0 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CC(C)=O>[C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2ccccc2C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: NC(=O)C1CNCCO1
Solvent: CC(C)=O
Product: O=C1CCCc2ccccc21

Procedure:
2-Tetralone-6-morpholinamide, ethylene ketal (323 mg, 1.06 mmol) and catalytic o-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. TLC indicated a mixture of 2-tetralone-6-morpholinamide, ethylene ketal and desired product, so the solution was heated to reflux for 16 hours. The volatiles were removed in vacuo and the residue applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 27 mg (10%) of 2-tetralone-6-morpholinamide a slowly crystallizing solid, pure by NNR, TLC. MS.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]2[C:9]3[CH:10]=[CH:11][C:12]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:26])[NH:5][CH2:4]1.[CH3:27]I.[H-].[Na+]>>[OH:1][CH2:2][C@H:3]1[N:8]2[C:9]3[CH:10]=[CH:11][C:12]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]4)=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1
Reactant: CI
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CN(C)C2=O)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-4-hydroxymethyl-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 12), methyl iodide and sodium hydride, to give the desired product as a colorless oil (16%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:5][C:6]1[C:11]([N:12]=[C:1]=[S:2])=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: Cc1ccc(N)c(Cl)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(N=C=S)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of thiophosgene (3.871 g, 33.66 mmol) in dichloromethane (10 mL) was added to a mixture of 2-chloro-6-methylpyridin-3-amine (4.00 g, 28.05 mmol) and sodium carbonate (5.947 g, 56.11 mmol) in dichloromethane (200 mL). The reaction was stirred overnight at ambient temperature, then washed with water, brine, dried, and concentrated to afford the desired product (5.2 g, 100.4% yield) as a tan powder.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([F:15])[F:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)Cc1ccc(OCC(F)F)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(OCC(F)F)cc1
Yield: 77.3 %

Procedure:
Step AX (2): 2-(4-(2,2-Difluoroethoxy)phenyl)acetic acid (6.00 g, 27.8 mmol) was deprotonated with NaHMDS (2.0 M in THF, 41.6 mL, 83 mmol) and reacted with 1-chloro-4-iodobutane (9.10 g, 41.6 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(2,2-difluoroethoxy)phenyl)hexanoic acid (6.94 g, 21.5 mmol, 77% yield) as a viscous oil that slowly solidified at rt to afford an off-white solid. LC-MS (M−H)− 305.21. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J=8.9 Hz, 2 H), 6.87 (d, J=8.5 Hz, 2 H), 5.88-6.23 (m, 1 H), 4.15 (td, J=13.0, 4.1 Hz, 2 H), 3.44-3.53 (m, 3 H), 1.99-2.12 (m, 1 H), 1.70-1.86 (m, 3 H), 1.31-1.50 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([CH2:29][CH3:30])=[N:22][C:23]([CH3:28])=[N:24][C:25]=1[CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([CH2:29][CH3:30])=[N:22][C:23]([CH3:28])=[N:24][C:25]=3[CH2:26][CH3:27])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CCc1nc(C)nc(CC)c1NC(=S)Nc1c(Cl)ccc(C(=O)OC)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(C)nc(CC)c1Nc1nc2c(Cl)ccc(C(=O)OC)c2n1CCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of the resulting thiourea (3.22 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.46 g, 7.59 mmol), and triethylamine (1.1 mL) in tetrahydrofuran (35 mL) was stirred at 60° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (2.90 g, 6.71 mmol, 52% in 2 steps).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:7]([Cl:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2]>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
To a solution of methyl[3,5-dichloro-4-(4-nitrophenoxy)phenyl] acetate (14 g) in ethyl acetate (90 mL) was added platinum(IV) oxide monohydrate (0.48 g) and the mixture was stirred vigorously under hydrogen gas (1 atmospheres) for 6 hours. The suspension was filtered and the filtrate concentrated. The residue was purified on column (silica gel, n-heptane/ethyl acetate, 1:1) to give 7.0 g of methyl[3,5-dichloro-4-(4-aminophenoxy)-phenyl] acetate as orange crystals.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[NH:19][CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:26]#N.[Na+]>C(O)(=O)C>[CH3:26][N:19]1[C:10]2=[CH:11][C:12]3[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:8]=[C:9]2[S:22][CH2:21][CH2:20]1
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline (11 mg, 0.033 mmol) and paraformaldehyde (9.9 mg, 0.33 mmol) in 0.5 mL acetic acid was added NaBH3CN (12 mg, 0.19 mmol). After 16 h, the solution was quenched with sat'd NaHCO3 (20 mL), and was extracted with EtOAc (20 mL). The organic layer was washed sequentially with sat'd NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to afford 11 mg (97%) of 2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline, a yellow solid. Data for 2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline: 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.01 (s, 1H), 6.98 (broad s, 1H), 5.45 (hept, 1H, J=6.2), 3.58-3.64 (m, 2H), 3.14-3.20 (m, 2H), 3.05 (s, 3H), 1.37 (d, 6H, j=6.2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:22][C:23]([C:25]1[C:34]([OH:35])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](C2C=CC3C(=CC=CC=3)C=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][OH:46])=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:22][C:23]([C:25]1[C:34]([OH:35])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:46][CH2:45][CH2:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[CH:8][CH:7]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc3ccccc3c2)cc1)NC(=O)c1cc2ccccc2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCc2ccc(Cl)cc2)cc1)NC(=O)c1cc2ccccc2cc1O
Yield: 39.7 %

Procedure:
0.05 g (0.1 mmol) of resin-bound 2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester obtained in Example 105 was reacted with 2-(4-chloro-phenyl)-ethanol (156 mg, 1.0 mmol), DIAD (1.0 mmol), Ph3P (1.0 mmol) in THF at rt overnight. The resulting resin was hydrolyzed according to general procedure C. The resin was then washed and cleaved as described in Example 28 to give the title compound (20 mg). LC/MS (m/z) 490 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25](O)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]([NH:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[C:3]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2
Reactant: O=C(O)Cn1c(=O)ccc2cc(Br)ccc21
Reactant: Nc1scc(Br)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2cc(Br)ccc21)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (55 mg, 224 umol) and 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid (85 mg, 301 umol) according to protocol A. HPLC purification gave 2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide. Method [7] retention time 5.41 min by HPLC (M+=508, 510, and 512). 1H NMR (300 MHz, CDCl3) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.63 (dd, J=9.0 and 2.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.94 (m, 2H), 5.31 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:17]=2[O:25]C)O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH:14]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:17]=3[O:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)cc(C)c1C(O)(c1ccc(C(C)C)cc1)C1CCN(Cc2ccccc2)CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1C)OC1(CCN(Cc3ccccc3)CC1)C2c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of (1-benzyl-4-piperidyl)(4-isopropylphenyl) (3,4,6-trimethyl-2-methoxyphenyl)methanol (5.61 g, 11.89 mmol) in acetic acid (40 ml) was added a 47% hydrobromic acid (50 ml) and the resulting mixture was refluxed with heating for 13 hours. The reaction mixture was cooled down to room temperature and then an 8 N aqueous solution of sodium hydroxide was added into the mixture until it became basic. The product was extracted with ethyl acetate. The extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from hexane to obtain 4.44 g (76% yield) of the title compound. Melting point: 125-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([C@@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[C:5]([CH3:21])[C:4]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][C:31]=2[O:30]1.[I-].[Li+]>CN(C)C=O.C(Cl)Cl>[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34][O:16][C:15](=[O:17])[C@H:14]([NH:13][S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[C:5]=3[CH3:21])(=[O:11])=[O:12])[C@@H:18]([OH:20])[CH3:19])=[CH:32][C:31]=2[O:30]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccc3c(c2)OCO3)[C@H](C)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyric acid (29.13 g, 87.9 mmol) in dimethylformamide (280 mL) at 0° C., was added potassium carbonate (72.9 g, 527 mmol) and a solution of 3,4-methylenedioxybenzyl chloride ((60 g, 170.8 mmol, 50% (w/w)) in methylene chloride. After 2 h, lithium iodide (5.88 g, 44 mmol) was added and the reaction mixture was warmed to rt. over 2 h. After 6 h, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (250 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxy-butyric acid 3,4-methylenedioxybenzyl ester (40.4 g), a portion which was taken directly into the next reaction without further purification.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[OH-].[Na+].I[CH3:15]>C(O)C.O>[CH3:15][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S1(=O)NC(=S)c2cscc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC1=NS(=O)(=O)c2cscc21
Yield: 36.3 %

Procedure:
To a mixture of 0.9 g (0.0044 mole) of thieno[3,4-d]isothiazol-3(2H)-thione 1,1-dioxide in 4 ml of ethanol is added a solution of 0.35 g (0.0044 mole) of 50% sodium hydroxide in 3 ml of water. To this thick mixture is added 0.62 g (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g of product. On cooling, a second crop of 0.1 g of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:15][C:14]([CH2:16][CH2:17][C:18]4[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=4)=[N:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C([O-])(=O)C.[NH4+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[NH:15][C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([NH:22][C:25](=[O:27])[CH3:26])=[CH:23][CH:24]=4)=[N:13][C:10]3=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(CCc2nc3ncc(-c4ccccc4)cc3[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCc2nc3ncc(-c4ccccc4)cc3[nH]2)cc1
Yield: 78 %

Procedure:
A solution of 4-(2-(6-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)aniline (Compound of Example 589) (25 mg) and acetic anhydride (0.01 ml) in pyridine was stirred at room temperature for 6 hours, and the reaction mixture was poured onto ice. The mixture was neutralized with a 5% aqueous solution of ammonium acetate and extracted with ethyl acetate. The organic layer was washed with water and dried over Na2SO4. The solvent was distilled off and the resulting crystals were collected by filtration to obtain N-(4-(2-(6-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)phenyl)acetamide (22 mg, 78%).