Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:13][CH2:14]Cl)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CO>[C:34]([CH:32]([CH:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[NH2:1][C:2]1[S:3][C:4]([CH2:13][CH2:14][N:25]2[CH2:24][CH:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Nc1nc(-c2ccccc2)c(CCCl)s1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccccc2)c(CCN2CC=C(c3ccccc3)CC2)s1
Temperature: 120 °C

Procedure:
20 mmol of 2-amino-5-(2-chloroethyl)-4-phenylthiazole and 20 mmol of 4-phenyl-1,2,3,6-tetrahydropyridine were thoroughly mixed and were heated under an N2 atmosphere at 120° C. until conversion was complete, which was the case after 20 minutes. After cooling, the solidified melt was stirred with water, the oily solid residue was separated off and stirred thoroughly with methanol and the solid was filtered off under suction. The filter residue was partitioned in 2 N NaOH/CH2Cl2 and the organic phase was separated off, dried and evaporated down. The residue was dissolved in methanol while hot, one equivalent of tartaric acid was added and the precipitated solid was filtered off under suction and purified by recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,5-bis-trifluoromethyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 60) was reacted with pyridine-4-yl-boronic acid to give the title compound as yellow amorphous solid. MS: 552.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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.CCOC(C)=O.O>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:8]1=[O:19]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1CCC(N2CCC(Cc3ccc(Br)cc3Cl)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(CC3CCN(C4CCC(=O)CC4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Combine 3-(4-Bromo-2-chloro-benzyl)-1-(4-oxo-cyclohexyl)-pyrrolidin-2-one (0.5, 1.3 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.814 g, 3.9 mmol), sodium carbonate (0.689 g, 6.5 mmol) in DME (8 mL)/H2O (3 mL) and degas with a stream of nitrogen. Add (Ph3P)4Pd (0.150 g, 0.13 mmol), and stir at 80° C. for 17 hour under nitrogen atmosphere. Cool to ambient temperature and add ethyl acetate (20 mL) and water (10 mL). Extract the aqueous phase with ethyl acetate (2×20 mL), dry (sodium sulfate) and condense under reduced pressure. Chromatography (silica, EtOAc) yields 0.287 g (42%) as a white solid MS (m/z): 386 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1.C(O)(=O)C.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:24]1([NH:8][C@H:9]2[C:16](=[O:17])[N:15]3[C@@H:11]([S:12][CH2:13][C@H:14]3[C:18]#[N:19])[CH2:10]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: N#C[C@@H]1CS[C@H]2C[C@@H](N)C(=O)N12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#C[C@@H]1CS[C@H]2C[C@@H](NC3CCCC3)C(=O)N12
Temperature: 45 °C

Procedure:
20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 μl of acetic acid, 6 μl of cyclopentanone and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45° C. for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% trifluoroacetic acid), linear gradient (0–>80% acetonitrile)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=5[F:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cc(F)ccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,5-difluoro-phenylboronic acid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@@H]3CCCN(S(C)(=O)=O)C3)cnc21

Procedure:
1-((R)-1-Methane sulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:32][CH:33]=1)=[O:27]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nn1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No.65202-50-8]. MS (m/e)=502.1 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1

Procedure:
A solution of 5.0 g (0.02 mol) of N-(4-bromophenyl)-α-chloroacetamide (Part A) and 5.05 mL (0.06 mol) of pyrrolidine in 100 mL of THF was stirred overnight at ambient temperature. The mixture was concentrated in vacuo and the residue was partitioned between H2O and EtOAc. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to afford 5.74 g of analytically pure title compound as crystals.
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]3[N:27]=[C:26]2[CH2:35][O:36]C)=[CH:20][CH:19]=1)=[O:11]>CO>[OH:36][CH2:35][C:26]1[N:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:10]([O:9][CH3:8])=[O:11])=[CH:19][CH:20]=2)[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]2[N:27]=1
Reactant: COCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(CO)nc3c(C)ccnc32)cc1
Yield: 75.5 %

Procedure:
50 ml (50 mmol) of a dichloromethane solution of 1M boron tribromide was added little by little dropwise to 100 ml of a dichloromethane solution of 3.3 g (8.2 mmol) of 3-[(2'-methoxycarbonyl-biphenyl-4-yl) methyl]-2-methoxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine, while stirred and cooled with ice. The mixture was further stirred at a room temperature for 12 hours. Methanol was added dropwise to the product mixture, while stirred and cooled with ice, and the solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with sodium bicarbonate. It was weakly acidified with acetic acid and decanted to remove the water. Methanol was added to the residue and distilled out at a reduced pressure. It was re-crystallized from ethanol-isopropylether to obtain 2.4 g of the intended compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COCC#Cc1ccc(-c2cnc3[nH]ccc3c2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCc1ccc(-c2cnc3[nH]ccc3c2)cn1
Yield: 77210.7 %

Procedure:
5-[6-(3-Methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine (43, 0.534 g, 2.03 mmol) was dissolved in 8.1 mL of methanol. Palladium hydroxide (0.028 g, 0.20 mmol) was added, and the resulting mixture was stirred under an atmosphere of hydrogen for a few hours, then filtered through a bed of celite. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (44, 419 g). MS (ESI) [M+H+]+=268.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12](N(CC)CC)[CH3:13].ICC>CN(C=O)C>[CH2:12]([S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: CCN(CC)CC
Reactant: O=S(O)c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylamine in 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90° C. for 9 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:7) to afford the title compound. MS (m/e): 206.9 (M+H+, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]=O)[C:5]#[N:6].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH2:25][CH2:26]1)[C:5]#[N:6]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1cc(C#N)ccc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C#N)ccc1/C=C/N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 3-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (188 mg, 0.8 mmol) and NaBH(OAc)3 in 25 mL of dry methanol were stirred at room temperature over night. The solid was filtered to get 160 mg of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.31˜7.40 (m, 5H), 6.72 (d, J=13.5 Hz, 1H), 5.35 (d, J=13.9 Hz, 1H), 3.20 (s, 4H), 2.95 (s, 2H), 2.57˜2.75 (m, 6H), 2.26 (s, 3H). MS m/z: 377 (M+1)+.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: C1CCNC1
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexyl methyl)-amide and pyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (t, J=6.01 Hz, 1H), 7.80 (d, J=9.21 Hz, 1H), 7.47-7.54 (m, 2H), 6.96 (d, J=9.22 Hz, 1H), 4.16 (s, 1H), 3.51-3.53 (m, 4H), 3.26-3.28 (m, 2H), 1.97-1.98 (m, 4H), 1.71-1.73 (m, 1H), 1.45-1.61 (m, 6H), 1.00-1.07 (m, 1H), 0.83-0.84 (m, 3H), 0.73-0.74 (m, 1H). m/z: 402.2 [M+H]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1.[CH3:53][C:54]1[O:58][C:57]([CH2:59][CH2:60]O)=[CH:56][CH:55]=1>C1COCC1>[CH3:53][C:54]1[O:58][C:57]([CH2:59][CH2:60][O:50][C:47]2[CH:46]=[CH:45][C:44]([C:43]([F:51])([F:52])[F:42])=[CH:49][CH:48]=2)=[CH:56][CH:55]=1
Reactant: Cc1ccc(CCO)o1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CCOc2ccc(C(F)(F)F)cc2)o1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of triphenylphosphine (1.56 g, 5.95 mmol) in THF (40 mL) was added DBAD (1.37 g, 5.95 mmol). After 10 min, 4-trifluoromethylphenol (0.964 g, 5.95 mmol) was added. After 10 additional minutes, compound 21A (0.500 g, 3.97 mmol) was added. After 14 h at 25° C., the reaction was concentrated in vacuo and purified by flash chromatography on silica eluting with chloroform to give 0.713 g (44%) of compound 232A as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][O:17]1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:24]([CH3:25])[CH3:23]
Reactant: CNC
Reactant: Clc1ccccc1CCCCc1ccccc1OCC1CO1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1Cl
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 1(b), 860 mg of 2-{2-[4-(2-chlorophenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran were treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified as described in Example 1(b), to give 790 mg (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([B:34]4[O:35][C:36]([CH3:38])([CH3:37])[C:32]([CH3:39])([CH3:31])[O:33]4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)OC1(C)C
Yield: 69.2 %

Procedure:
3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (15.0 g, 40.6 mmol) was combined with dioxane (350 mL) at rt under N2. Et3N (34.0 mL, 24.7 g, 244 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.4 mL, 9.37 g, 73.2 mmol) were added to the mixture by syringe. trans-Dichlorobis(triphenylphosphine)palladium(II) (1.44 g, 2.04 mmol) was added and Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was refluxed under N2 for 18 h. The cooled reaction mixture was concentrated and the residue was combined with EtOAc (500 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The crude product (22.9 g) was recrystallized from CH3OH (50 mL) to give 3-benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (11.7 g) in 69% yield. MS (ESI+) for C25H29BN2O3 m/z 417.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([F:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[Cl:19][C:4]([C:3]1[C:2]([F:1])=[CH:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7]=1[F:15])=[O:5]
Reactant: COC(=O)c1cc(F)c(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 2,6-difluoro-4-(methoxycarbonyl)benzoic acid (1.6 gm, 7.4 mmol) in dichloromethane (25 mL), oxalyl chloride (2.33 gm, 18.5 mmol) was added at 0° C. followed by addition of dimethylformamide (1 mL). The resulting reaction mixture was stirred for about 3 hours at an ambient temperature. Solvents were evaporated to afford crude solid methyl 4-(chlorocarbonyl)-3,5-difluorobenzoate (1.6 gm, 94.11% Yield). The resulting product was used as such for next step.
Reaction SMILES: [Li].N.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:10]([CH3:25])[C:9]([CH3:27])([CH3:26])[C:8]1[CH2:28][CH2:29][CH2:30][C:31](=[O:32])[C:7]2=1>O1CCCC1>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:10]([CH3:25])[C:9]([CH3:26])([CH3:27])[C@@H:8]1[CH2:28][CH2:29][CH2:30][C:31](=[O:32])[C@@H:7]21
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1=O)C(C)(C)N2C
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)c1cc2c(cc1O)[C@@H]1C(=O)CCC[C@H]1C(C)(C)N2C

Procedure:
Lithium metal, 1.2 g., in 1000 ml. of anhydrous ammonia and 4.03 g. (10 mmole) of 5,6,7,8,9,10-hexahydro-2-hydroxy-3-(1-methyl-4-phenylbutyl)-10-oxo-5,6,6-trimethylbenzo[c]quinoline in 500 ml. of tetrahydrofuran were reacted by the procedure of Example 9 and the resulting mixture of 6a,10a-cis and 6a,10a-trans isomers was isolated and separated by silica gel chromatography as described therein.
Reaction SMILES: [C:1]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]([CH2:18]N(C)C)[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:22]([O-:49])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(#N)C>[C:1]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]([CH:10]=1)[CH2:18][P:22](=[O:49])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(CN(C)C)cc(C(C)(C)CC(C)(C)C)c(O)c1C
Reactant: CCCCCCCCCCCCOP([O-])OCCCCCCCCCCCC
Solvent: CC#N
Product: CCCCCCCCCCCCOP(=O)(Cc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1C)OCCCCCCCCCCCC

Procedure:
This compound was made in a similar manner as Example 5 by reacting 6-tert.-octyl-2,3-dimethyl-4-(dimethylaminomethyl)phenol (Example 2) with di-n-dodecyl phosphite. After trituration with acetonitrile, the desired compound is obtained as white crystals melting at 36° to 40°C (Compound 7).
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].[CH2:5]([C:7]1(Cl)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].Cl>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:7]1([CH2:5][CH3:6])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=C(Cl)Cl
Reactant: CCC1(Cl)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C=C(Cl)Cl)CCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
10 g of anhydrous aluminum chloride were added to 291 g (3 mol) of 1,1-dichloroethene at -20° C., and thereafter 133 g (1 mol) of 1-ethyl-cyclopentyl chloride (Chem. Abstr. 42, 6,328 (1948)) were added dropwise at 0° to 10° C. The reaction solution was allowed to warm up to 20° C., a further 5 g of aluminum chloride were added, and stirring was continued for a further 2 hours at 20° C. The mixture was poured onto ice, and was worked up with methylene chloride and dilute hydrochloric acid. 158 g (82% of theory) of 1-(2,2-dichlorovinyl)-1-ethylcyclopentane of boiling point 45° to 50° C./0.1 mm Hg were obtained by fractional distillation of the organic phase after it had been dried over sodium sulphate. ##STR20##