Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[O:15][CH2:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18])([CH3:12])[CH3:11].O>ClCCCl.CCCCCC>[CH:10]([C:13]1[CH:32]=[C:31]([C:3](=[O:4])[CH2:2][Cl:1])[CH:30]=[CH:29][C:14]=1[O:15][CH2:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: O
Product: CC(C)c1cc(C(=O)CCl)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 0.33 h

Procedure:
To a solution of chloroacetyl chloride (10.0 ml) in anhydrous 1,2-dichloroethane (250 ml) is added aluminum chloride (12 g) at room temperature, and the mixture is stirred for 20 minutes. To the mixture is added at once 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (20 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into water, and thereto is added n-hexane. The precipitates are collected by filtration, washed with water, and dried to give 2-[2-isopropyl-4-(2-chloroacetyl)phenoxymethylcarbonylamino]benzothiazole (25.9 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:16]([O:18][C:19]([C:21]1[NH:29][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([C:21]1[N:29]([CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Yield: 28.9 %

Procedure:
(3-Bromo-propoxy)-triisopropyl-silane (209 mg, 0.71 mmol) was dissolved in DMF (5 ml) and 3-(2-fluoro-4-iodophenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.59 mmol) was added, followed by cesium carbonate (250 mg, 0.77 mmol). The mixture was heated at 80° C. under nitrogen for 3 hours, then allowed to cool, diluted with water and extracted with dichloromethane (×2). The combined organic layers were washed with 20% aqueous lithium chloride solution, dried over magnesium sulfate then concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:methanol gradient 1:0 to 99:1) gave the title compound as a yellow oil (109 mg, 44%). LCMS (method B): RT 3.41, M+H+ 640.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:21][CH2:22][N:23]([C:33]([NH:32][C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:24][CH2:25]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)ccc2Cl)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2ccc(Cl)c(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
To a solution of 2-(2-chloro-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (250 mg, 0.677 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (137.9 mg, 0.643 mmol) followed by triethylamine (0.24 mL, 1.69 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% acetone-70% hexane) to give the pure title compound (180 mg, 54% yield). 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.95 (d, J=7 Hz, 1H), 7.33 (s, 1H), 7.18 (d, J=3.5 Hz, 2H), 7.12 (d, J=8 Hz, 1H), 6.72 (s, 1H), 6.37 (s, 1H), 3.64 (m, 2H), 3.56 (m, 2H), 2.62 (m, 2H), 2.49 (m, 2H); 13C NMR (125 MHz, CDCl3): δ164.98, 154.54, 147.45, 145.35, 145.32, 143.84, 141.01, 138.68, 136.94, 136.22, 136.10, 130.79, 128.50, 127.62, 127.07, 126.69, 123.61, 123.45, 122.05, 121.78, 111.19, 45.68, 44.61, 40.91, 35.69, 29.14, 28.47; m/z (489.3, 491.1 M+ H+); HPLC: 96.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:18].CS(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[O:18][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cn3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A mixture of 2-fluoro-4-[5-(methylsulfonyl)-2-pyridinyl]phenol (0.114 g, 0.43 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (0.18 g, 0.55 mmol) and K2CO3 (0.12 g, 0.85 mmol) in DMF (5 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight. Cooled to ambient temperature, the mixture was poured into water (30 mL), and the precipitate was collected, washed with water and air dried. The solid was further triturated with hot MeOH to give 0.125 g (65%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J=1.7 Hz), 8.23 (dd, 1H, Ja=8.4 Hz, Jb=2.0 Hz), 7.90-7.75 (m, 3H), 7.05 (t, 1H, J=8.4 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.94 (d, 2H, J=6.6 Hz), 3.13 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H), 1.24 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 451 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([OH:15])[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cnc(Cl)nc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-5-fluoropyrimidine (100 mg, CAS 2927-71-1) was combined with trifluoroethanol (1.09 ml) to give a colourless solution. Potassium carbonate (82.8 mg) was added. The reaction mixture was stirred at room temperature for 30 min. TLC at t=30 min showed the reaction was complete. The reaction mixture was filtered through sintered glass and concentrated in vacuo. The residue was triturated with diethyl ether, then filtered through sintered glass and dried in vacuo.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22](Br)[C:17]=2[O:16][CH2:15]1>>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:10]3([OH:11])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=4)[NH:3][C:2]3=[O:1])[C:17]=2[O:16][CH2:15]1
Reactant: Brc1cccc2c1OCO2
Reactant: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Product: N#Cc1ccc2c(c1)C(O)(c1cccc3c1OCO3)C(=O)N2

Procedure:
With 1.70 g of 2,3-dioxo indoline-5-carbonitrile and 1,3-benzodioxol-4-yl bromide (13 ml) as starting materials, 1.37 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH:13]([OH:15])[CH3:14])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].II.[H][H].[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(O)CNC(=O)Cc1ccc(Cl)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
2-(4-Chlorophenyl)-N-(2-hydroxypropyl)acetamide (5.0 g, 21.96 mmol, 1.00 eq), tetrahydrofuran (THF, 7.5 mL), and sodium borohydride (1.662 g, 43.9 mmol, 2.00 eq) were charged to a 100 mL round bottomed flask. The resulting stirred white suspension was cooled to −10° C., and a solution of iodine (5.574 g, 21.96 mmol, 1.00 eq) in THF (10 mL) was added dropwise over 30 minutes while cooling of the reaction suspension was continued. Hydrogen gas evolved during the addition. After the addition, the dark brown reaction suspension was heated and stirred at 70° C. until 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide conversion was substantially complete. Such conversion was achieved in 3.5 hours at 70° C. The reaction mixture was cooled to 0° C., and methanol (15 mL) was added sufficiently slowly to maintain the stirred reaction mixture at about 0° C. with external cooling. The methanol addition was initially accompanied by fairly vigorous evolution of gas. After the resulting mixture had been heated at 65° C. for 0.5 hr, solvents were evaporated under vacuum. To the residual white slurry was added 50 wt % aqueous NaOH (15 mL, 286 mmol, 13 eq) while the stirred product mixture was maintained at 0° C. The resulting mixture was heated with stirring at 80° C. for 1.5 hr. After 0.5 hr of such heating, mild foaming stopped, and a mixture of two clear, homogenous layers was obtained. Toluene (20 mL) was added, and the resulting mixture was heated and stirred at 50° C. to extract the product into toluene. The lower aqueous layer was drained, and the upper organic layer was washed with water (two 15 mL portions). The washed organic layer was evaporated to dryness under vacuum at 60° C. Vacuum drying of the evaporation residue at 60° C. was continued for 2 hr to yield intermediate 1-(4-chlorophenethylamino)-propan-2-ol as an off-white solid (4.23 g, 90.1% yield, 96.17% purity by HPLC peak area). To the intermediate 1-(4-chlorophenethylamino)propan-2-ol in a round bottomed flask was added toluene (20 mL). (One skilled in the art can achieve substantially the same water-free mixture of intermediate 1-(4-chlorophenethylamino)propan-2-ol in toluene by azeotropic removal of water without evaporation of the majority of the toluene.)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.CCCCCC.[CH3:18][C:19]1([CH3:31])[CH2:28][C:27](=O)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:30])[CH:25]=2)[O:20]1>C1COCC1.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:31])[CH:28]=[C:27]([C:4]2[S:3][C:2]([CH3:1])=[CH:6][CH:5]=2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:30])[CH:25]=2)[O:20]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (-78° C.) solution of 2-methylthiophene (820 mg, 8.3 mmol) in THF (16 mL) was added n-BuLi in hexane (1.6M, 4.4 mL, 8.5 mmol). The mixture was warmed to ambient temperature and stirred for 15 minutes. This solution was added to a flask containing cold (-78° C.) solution of 2,2-dimethyl-6-bromo-chroman-4-one (1.08 g, 4.2 mmol) in THF (4 mL). The mixture was stirred and allowed to gradually warm to ambient temperature over 8 hours, and then stirred for an additional 4 hours at ambient temperature. The mixture was diluted with ethyl acetate (200 mL), washed with 10% HCl, brine (20 mL), dried and the solvent was removed by evaporation. The product was purified by chromatography on a silica gel column to afford the title compound as a colorless oil.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][C:27]([C:48]#[N:49])=[N:28][C:29]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:12][C@@H:11]1[C:50]([NH:52][CH2:53][CH3:54])=[O:51])(=O)C1C=CC=CC=1.N>[Pd].C(O)C>[NH2:49][CH2:48][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[C@@H:13]2[O:12][C@H:11]([C:50]([NH:52][CH2:53][CH3:54])=[O:51])[C@@H:10]([OH:9])[C@H:14]2[OH:15])=[C:29]([NH:33][CH2:34][CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:28]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
10% Palladium on carbon (400 mg) was added to a solution of (2S,3S,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 7) (2.0 g, 2.70 mmol) in a saturated solution of ammonia in ethanol (40 ml). The reaction mixture was stirred under an atmosphere of hydrogen (414 kPa, 60 psi) for 16 hours at room temperature. The suspension was filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing to (90:10:1 by volume). This gave the title compound as a solid (1.2 g).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]([OH:16])[C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[CH:14][S:13][C:12]=23)[CH:4]=[N:3][CH:2]=1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[C:5]([C:7]([C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[C:14]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[S:13][C:12]=23)=[O:16])[CH:4]=[N:3][CH:2]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: OC(c1cncnc1)c1ncn2ccsc12
Agent: [Mn+4]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncnc3)c2s1

Procedure:
A ketone compound (217 mg) was prepared in substantially the same manner as in step b) of Synthesis Example 1, except that 398 mg of 7-[(pyrimidin-5-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 400 mg of manganese dioxide were used as the starting compounds. 7-(Pyrimidin-5-yl)carbonyl-2-(tri-n-butylstannyl)-imidazo[5,1-b]thiazole (68 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 46 mg of the ketone compound, 0.124 ml of tri-n-butylstannyl chloride, and 0.900 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[C:3](=[O:13])[CH2:4][CH2:5][CH2:6]1>[Pd].CO>[CH:1]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]1[CH:2]2[C:3](=[O:13])[CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCC2C3C=CC(CC3)C12
Agent: [Pd]
Solvent: CO
Product: O=C1CCCC2C3CCC(CC3)C12
Reaction time: 1 h
Yield: 86 %

Procedure:
In a single-neck 100 ml flask, tricyclo[6.2.2.02,7 ]dodec-9-en-3-one (10 g, 56.81 mmole) was admixed with methanol (20 ml). There was then added 5% Pd/C (0.1 g) and the catalytic hydrogenation was carried out at atmospheric pressure during 1 h (stirring: 2000/rot/min). After filtration, concentration and bulb-to-bulb distillation (B.p. 120°/5hPa), 8.7 g (48.87 mmole) of the desired dodecanone were obtained (yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:32])([F:33])[F:31])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:19][CH3:20])=[C:6]([CH:12]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14][O:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14][O:13]2)[C:5]([O:19][CH3:20])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CNC(=O)CO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C)c1C1CNC(=O)CO1
Reaction time: 1 h

Procedure:
To a solution of 6-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)morpholin-3-one (27 mg, 0.090 mmol) (single enantiomer from step 4) in methanol (2 mL) was added sodium tetrahydroborate (6.8 mg, 0.18 mmol) at 0° C. and stirred for 1 hour. Purification by preparative LCMS (pH 10) gave the desired compound as a racemic mixture of two diastereomers, 20 mg, 76%. LCMS calculated for C14H17ClNO3 (M-OH)+: m/z=282.1; found: 282.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1F.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Reactant: Nc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1Nc1ccccc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 84.4 %

Procedure:
4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0° C. in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH2Cl2 and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (−) m/z 320.3 (M−1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: NC(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Yield: 82.6 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 7, step (d) using 3-(4-amino-3-bromo-phenyl)-propionamide (as prepared in Example 7, step (c), 76.0 mg, 0.351 mmol), and 4,4-dimethylcyclohexen-1-yl boronic acid (59.5 mg, 0.387 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (79 mg, 92%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H24N2O, 273.2 (M+H). found 273.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O>CC(O)C.[Pd]>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)cc1O
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)cc1O
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH).
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]([S:16][C:22]2[C:21]3[C:25](=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Sc1cccc(Br)c1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1ccc2c(Sc3cccc(Br)c3)c[nH]c2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-chlorosuccinimide (1.93 g, 14.5 mmol) was dissolved in DCM (120 mL) and cooled to −78° C. 3-Bromothiophenol was added and the reaction was warmed to 0° C. After 1 hour, a solution of 6-chloroindole (2.0 g, 13.2 mmol) in DCM (20 mL) was added via canula. The reaction was stirred at 0° C. for 3 hours after which time it was submitted to aqueous workup and purification by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[CH:11]([OH:13])[CH3:12].[CH2:14]([OH:16])[CH3:15]>[Fe]>[C:14]([O:13][CH:11]([C:4]1[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[Cl:2])[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: CCO
Agent: [Fe]
Agent: Cl
Product: CC(=O)OC(C)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C

Procedure:
2 M HCl (0.2 mL) is added to solution of compound A1 (0.97 mmol) in 2 mL of ethanol. The mixture is then put in an ice bath and Fe powder (365 mg) is added slowly. The reaction is heated to 85° C. for 1 hr and cooled to room temperature. Celite (0.5 g) is added to stir and the resulting mixture is filtered through a bed of celite and rinsed with ethanol. The filtrated is evaporated to give a brown oil residue, compound A2. The residue is used without further purification.