Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=3)[CH:9]=2)[C:4]1=[O:22])[CH3:2].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:22])[C:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:1][CH3:2])[CH2:12][CH2:11]3)=[N:14][CH:15]=1
Reactant: CCOC(=O)CC1(CC)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(CC)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 85.3 %

Procedure:
Iron powder (1.533 g, 27.5 mmol) was added to a solution of 4F (2.1 g, 5.49 mmol) in 30 mL of ethanol-water mixture (5:1) followed by NH4Cl (0.015 g, 0.275 mmol), and the mixture was refluxed for 5 h. The solvent was removed under reduced pressure, and residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 40% ethyl acetate in hexane to afford the title compound (1.65 g, 85%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=2.7 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.06 (dd, J1=2.7 Hz, J2=8.4 Hz, 1H), 4.11 (q, J=5.7 Hz, 2H), 3.84 (bs, 2H), 3.23-3.12 (m, 1H), 3.06-2.93 (m, 2H), 2.56-2.46 (m, 2H), 2.14-2.07 (m, 1H), 1.85-1.61 (m, 2H), 1.24 (t, J=6.9 Hz, 3H), 0.92 (t, J=7.8 Hz, 3H). ESI-MS m/z=353 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(C)(C)CC(=O)O)ccc1OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of STEP 8 (67.5 mg, 0.17 mmol) was dissolved in 5 ml methanol and 5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 16 h, and acidified with trifluoroacetic acid (1.0 ml). Solvents were evaporated and residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 31.5 mg. FAB-MS: (MH+)=373. H NMR(CDCl3) δ1.03 (s, 6H), 2.21 (p, 2H), 2.22 (s, 2H), 2.61 (s, 2H), 3.60 (q, 2H), 3.84 (s, 2H), 4.13 (t, 2H), 6.65-6.82 (m, 4H), 6.96 (d, 1H), 7.68-7.80 (m, 2H); Anal Calcd. for C21H28N2O4 plus 1.5 CF3COOH: C, 52.17; H, 5.56; N, 5.07. Found: C, 52.44; H, 5.62; N, 4.88.
Reaction SMILES: [C:1]([CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][OH:6])#[N:2].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[C:1]([CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][O:6][CH3:17])#[N:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](CC#N)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution in tetrahydrofuran (10 mL) of the compound (650 mg) obtained in step (1) above, sodium hydride (60% dispersion in mineral oil, 143 mg) was added under cooling with ice. After stirring the mixture at the same temperature for 10 minutes, methyl iodide (603 μL) was added. After stirring the mixture at the same temperature for 30 minutes and then at room temperature for an hour, water was added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-60:40) to give tert-butyl [(2S)-1-cyano-3-methoxypropan-2-yl]carbamate as a colorless oil (247 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(ccc(Br)c2F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1c(Br)ccc2c1CCC(=S)N2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-fluoro-3,4-dihydroquinolin-2(1H)-one (146-5; 0.45 g, 0.00184 mol) in toluene (10 mL) was added Lawesson's reagent (0.745 g, 1.00184 mol). Reaction mass heated at 120° C. and maintained for 2 h. The reaction mixture was cooled, quenched with sodium bicarbonate solution and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 12.364 (s, 1H), 7.543-7.503 (t, J=8.0 Hz, 1H), 6.895-6.874 (d, J=0.1-8.4 Hz, 1H) 2.968-2.930 (t, J=7.2 Hz, 2H), 2.843-2.805 J 8.0 Hz, 2H): MS (M 1): 260.1.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[CH2:7]([NH:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][CH:23]=[CH2:24])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:25]([O-])=O)[CH:17]=2)[N:12]=1)[CH:8]=[CH2:9].[OH-].[Na+]>>[CH2:7]([NH:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][CH:23]=[CH2:24])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:25])[CH:17]=2)[N:12]=1)[CH:8]=[CH2:9]
Reactant: C=CCNc1nc(NCC=C)c2cc([N+](=O)[O-])ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: C=CCNc1nc(NCC=C)c2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3.32 g (14.73 mmol) of tin (II) chloride dihydrate was added 14 ml of concentrated hydrochloric acid and 1.40 g (4.91 mmol) of 2,4-diallylamino-6-nitroquinazoline under ice cooling, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution, followed by extraction with chloroform, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 1.61 g (yield: 92.5%) of a free base compound of the title compound.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@@H:16]1[CH2:21][CH2:20][C@@H:19]([CH3:22])[CH2:18][C@H:17]1[CH3:23])=[O:15])C1C=CC=CC=1.OO.[Li+].[OH-].[O-:28]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:23][C@@H:17]1[CH2:18][C@H:19]([CH3:22])[CH2:20][CH2:21][C@H:16]1[C:14]([OH:15])=[O:28]
Reactant: C[C@@H]1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](C)C1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](C(=O)O)[C@H](C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-4-benzyl-3-((1R,2R,4R)-2,4-dimethylcyclohexanecarbonyl) oxazolidin-2-one (0.65 g, 2.0 mmol) in THF/water (3:1, 20 mL) was cooled in an ice bath and 30% H2O2 (1 mL, 16.5 mmol) was slowly added, followed by LiOH*H2O(s) (0.17 g, 4.0 mmol) in one portion. The reaction was allowed to slowly warm to room temperature and stirred for 16 h. The reaction was then cooled in an ice bath. A 1 M solution of Na2SO3 was very slowly added to the cooled reaction mixture. The solution was stirred for 1 h, and the layers were separated. The organics were removed under reduced pressure. The aqueous was added back to the organics concentrate and was washed with CH2Cl2 (2×50 mL). The pH of the aqueous solution was adjusted to 2 through slow addition of concentrated hydrochloric acid. The resulting mixture was extracted with EtOAc (1×50 mL) and dried over Na2SO4. Solvents were removed under reduced pressure, co-evaporating with hexanes, to afford 0.300 g of (1R,2R,4R)-2,4-dimethylcyclohexanecarboxylic acid as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CCOCC>[C:36]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)N(C(C)=O)CC2
Reaction time: 2 h
Yield: 96 %

Procedure:
A stirred solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.8942 g, 5.0720 mmoles) in methylene chloride (15 mL) at 0° C. was treated with triethylamine (0.707 mL, 1.5 equiv.) and acetic anhydride (0.844 mL, 1.5 equiv.). After 2 hours at room temperature, The mixture was diluted with ether and washed with 1M sodium hydroxide (2×), water, and brine. The organic phase was dried over sodium sulfate and evaporated to give the product as a colorless foam (2.0178 g, 96%). 1H-NMR (CDCl3) δ (approx. 1.8:1 ratio of rotomers) 1.65 (rotomer A, s, 3H), 1.96 (rotomer B, s, 3H), 2.35 (rotomer B, m, 1H), 2.54 (rotomer A, m, 1H), 2.67 (rotomer A, m, 1H), 2.80 (rotomers A & B, m, 1H), 2.94 (rotomer A, m, 1H), 3.21 (rotomer A, m, 1H), 3.43 (rotomers A & B, m, 1H), 3.77 (rotomer B, s, 3H), 3.88 (rotomers A & B, s, 3H), 3.92 (rotomer A, s, 3H), 4.03 (rotomer A, m, 1H), 4.12 (rotomer B, t, 1H), 4.60 (rotomer B, m, 1H), 5.68 (rotomer A, m, 1H), 6.38 (rotomer B, s, 1H), 6.53 (rotomer A, s, 1H), 6.60 (rotomer B, s, 1H), 6.62 (rotomer A, s, 1H), 7.32 (rotomers A & B, m, 10H). Mass spec. 416.4 (MH)+. Anal. Calc. for C27H29NO3-2/3H2O: C-75.85, H-7.15, N-3.28. Found: C-75.89, H-7.03, N-3.24.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH2:15][C:16]([NH2:18])=[O:17]>C(O)C>[C:7]1([C:6]2[N:18]=[C:16]([OH:17])[N:15]=[C:4]([OH:14])[CH:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(O)n1
Temperature: 30 °C

Procedure:
A mixture of 3-oxo-3-phenylpropionic acid ethyl ester (20 g, 104.05 mmol) and urea (6.24 g, 104.05 mmol) was reacted in a microwave irradiation for 3 minutes. The mixture was cooled to temperature in the range of 20-40° C. and diluted with ethyl alcohol (100 mL). The solid precipitated was filtered, washed with hexane (2×20 mL) to afford the desired compound as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]([CH:10]=[O:11])[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH:5]=1>C(O)C>[CH3:3][C:4]1[CH:9]([CH2:10][OH:11])[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH:5]=1
Reactant: CC1=CCCC(C)(C)C1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=CCCC(C)(C)C1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a suspension of 1.25 g NaBH4 in 50 ml. 95% ethanol cooled in an ice bath was added dropwise with stirring 5.0 g alpha-cyclocitral which had been prepared as described in Example 1. When the addition was complete, the ice bath was removed and water was added to dissolve any remaining solids. The reaction mixture was then stirred overnight at room temperature. The solvent was removed at reduced pressure and the residue taken up in ether, washed with 1 N acetic acid, dilute sodium bicarbonate and water. The ether extract was dried over sodium sulfate and concentrated to give 3.6 g alpha-cyclogeraniol as a colorless oil of 95% purity by gas chromatographic analysis.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([C:29]6[N:33]=[C:32]([CH3:34])[NH:31][N:30]=6)[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.Br[CH2:38][CH2:39][O:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([C:29]6[N:33]=[C:32]([CH3:34])[N:31]([CH2:38][CH2:39][O:40][CH3:41])[N:30]=6)[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: COCCBr
Reactant: Cc1nc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4C)n3c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4C)n3c2)nc1C

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F79) (6.0 mg, 0.012 mmol), 1-bromo-2-methoxyethane (1.7 mg, 0.012 mmol) and K2CO3(5.0 mg, 0.036 mmol) in DMF (0.5 mL) was heated at 120° C. for 30 minutes. The reaction mixture was purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(1-(2-methoxyethyl)-5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F99). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 10.11 (m, 1H), 8.65 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 8.06 (dd, J=2.0, 9.2 Hz, 1H), 7.88 (dd, J=0.8, 9.2 Hz, 1H), 7.85 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 4.34 (t, J=5.2 Hz, 2H), 3.89 (m, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.24 (s, 3H), 3.02-3.20 (m, 4H), 2.47 (s, 3H), 2.39 (s, 3H). MS m/z 549.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]C)=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cccc2nccn12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1-c1cccc2nccn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred solution of 5-(5-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine (1.82 g, 7.03 mmol) in dichloromethane (30 mL) at −78° C. was added boron tribromide (1.0 mL, 10.6 mmol). The mixture was allowed to warm to ambient temperature and stirred for 4 h and cooled to 0° C. The reaction mixture was cautiously diluted with water and the pH was adjusted to >7 by the addition of 2 M aqueous sodium carbonate, causing a precipitate to be deposited. The solid was collected by filtration and washed sequentially with water, dichloromethane and diethyl ether to afford 4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenol as a colorless solid in 73% yield (1.26 g): 1H NMR (300 MHz, DMSO-d6) δ10.41 (s, 1H), 7.72-7.55 (m, 2H), 7.55-7.28 (m, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.91 (d, J=6.9 Hz, 1H); MS (ES+) m/z 245.0 (M+1), 247.0 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[C:22]1([C:28]2([NH:34][C:35](=[O:37])[CH3:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S1C=CC=C1>CC(O)C.[Pt].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:35]([NH:34][C:28]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30][N:31]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:3]2)[CH2:32][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccccc1
Agent: [Pt]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: c1ccsc1
Solvent: CC(C)O
Product: CC(=O)NC1(c2ccccc2)CCN(C2CCN(C(=O)OC(C)(C)C)C(Cc3ccccc3)C2)CC1
Yield: 81.4 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-oxo-2-(phenylmethyl)-1-piperidine carboxylate (0.1 mol) and N-(4-phenyl-4-piperidinyl)acetamide (0.1 mol) in 2-propanol (500 ml) was hydrogenated at 50° C. with platinum (4 g) as a catalyst in the presence of titanium(IV)isopropoxide (28.5 g) and thiophene (4%; 1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 40 g (74.1%) of (±)-1,1-dimethylethyl 4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(phenylmethyl)-1-piperidinecarboxylate (intermediate 19).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([NH:26][C:15]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)O
Reactant: CCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@@H]1CCCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-(−)-1-(tert-Butoxycarbonyl)-2-azepanecarboxylic acid (prepared as described in Tetrahedron Letters (1994), 35(2), 237–240) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. n-Octylamine (0.584 g; 4.52 mmol), N,N-diisopropylethylamine (1.17 g; 9.04 mmol) and PyBOP (2.35 g; 4.52 mmol) are added sequentially. The reaction is stirred for 24 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silca gel chromatography affording the desired product (2).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=3)[C:5]=2[N:6]=1.Cl.Cl.[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH:24]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([C:7]2[C:5]3[N:6]=[C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([C:25]5[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=5)[CH2:30][CH2:31]4)[S:3][C:4]=3[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(Br)sc2c1
Agent: Cl
Product: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)sc2c1

Procedure:
Prepared in analogy to example 207d, starting from 2-bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole and 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.CN(C)CCN(C)C.[Li]CCCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([CH2:11][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[OH:38])[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (1.33 g, 4.91 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.74 mL, 5.40 mmol) in anhydrous THF (50 mL) was added a solution of n-BuLi (2.5 M in hexanes, 2.4 mL, 6.0 mmol) dropwise at −78° C. The reaction mixture was stirred for 15 min, then a solution of benzaldehyde (0.65 mL, 6.29 mmol) in anhydrous THF (5 mL) was added rapidly. The mixture was stirred at −78° C. for 15 min, then allowed to warm to RT and partitioned between EtOAc and H2O. The organic layer was isolated, washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (1.20 g, 66%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[O:17]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:19]2[CH:20]=[CH:21][O:17][CH:18]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccoc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccoc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and furan-3-carboxylic acid
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[O:13][CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[B:21](F)([F:23])[F:22]>>[B:21]([F:23])([F:22])[O:18][C:17]([C:5]1[C:4](=[O:20])[C:3]2[C:8]3=[C:9]([O:13][CH2:14][CH:15]([CH3:16])[N:7]3[CH:6]=1)[CH:10]=[C:11]([F:12])[C:2]=2[F:1])=[O:19]
Reactant: CC1COc2cc(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Reactant: FB(F)F
Product: CC1COc2cc(F)c(F)c3c(=O)c(C(=O)OB(F)F)cn1c23

Procedure:
From 1.0 g of 8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (for preparation see Journal of Medicinal Chemistry 1992, 35 (4), 611) and 1.51 g (3 eq.) of BF3 etherate, by the same method as described for Example 38A, 1.0 g (85% of theory) of the title compound is isolated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=2.[O:18]([C:25]1[CH:30]=[CH:29][C:28](O)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N1C2C(=CC=CC=2)C=C1>C1COCC1>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([CH2:3][CH2:2][O:1][C:28]1[CH:29]=[CH:30][C:25]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:26][C:27]=1[CH2:32][CH2:33][CH3:34])=[CH:12]2
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCc1cc2cc(CC(=O)OC)ccc2[nH]1
Yield: 62.3 %

Procedure:
A solution of methyl 2-(2-hydroxyethyl)indole-5-acetate from Example 1, Step E (7.6 g), 4-phenoxy-2-propylphenol (8.28 g), triphenylphosphine (11.2 g), DIAD (8.5 mL) and THF (125 mL) was stirred under nitrogen at room temperature. After stirring overnight none of the starting indole remained as determined by TLC and the reaction was concentrated to a yellow oil. The oil was purified by silca gel chromatography (10%-20% ethyl acetate in hexanes) to give the desired product (9.0 g).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A 4-piperidone hydrochloride monohydrate (15.3 g) was dissolved in 2N aqueous solution of sodium hydroxide (100 mL). To the solution was added a benzyloxycarbonyl chloride (20.4 g) at 0° C. The mixture was stirred for 1 hour. The reaction mixture was neutralized with 2N hydrochloric acid, and the aqueous solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated to give the title compound (23.3 g) having the following physical data.