Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(OC(C)C)(C)C>[CH2:29]([NH:32][C:33]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:34])[CH:30]=[CH2:31]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: C=CCN=C=O
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CC(C)OC(C)C
Product: C=CCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A solution of 18.9 g (0.05 mole) of crude 3-[3-(trifluoromethyl)phenoxy]azetidine (contains an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether was stirred under nitrogen while 4.16 g (0.05 mole) of 2-propenyl isocyanate was slowly added. The reaction mixture which was somewhat turbid, cleared and after 1 hr a fine crystalline precipitate began to form. After stirring for 18 hrs, the product was removed by filtration, washed with fresh isopropyl ether and air dried to yield 9.5 g of white crystals, m.p. 75°-76° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])O[C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:12](=[O:17])[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][C:14]2=[O:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(c3ccc([N+](=O)[O-])cc3)CC2=O)cc1
Temperature: 85 °C
Yield: 669 %

Procedure:
A solution of 12.6 g (53.6 mmol) of 4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in the previous step) in THF (160 mL) was treated with 9.04 mL (6.96 mmol) of 4-methoxy-benzylamine at RT for 2 h. Solvents were evaporated in vacuo. The residue was dissolved in 1.0 N HCl (200 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (1×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was treated with acetic anhydride (200 mL) and triethylamine (30 mL), and heated to 85° C. for 1.5 h. The mixture was concentrated in vacuo, treated with 1.0 N HCl (200 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1×200 mL) and water (1×200 mL), dried (MgSO4), and concentrated in vacuo. The solid was triturated with hexane using sonication, filtered and air-dried to afford 16.5 g (87%) of the title compound as light tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H21N2O, 325.1 (M-OCH3+2H). found 325.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[N:15]([C:25]2[N:26]=[CH:27][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:29][N:30]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1)S(C)(=O)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Yield: 77.7 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1-piperazinecarboxylate (0.498 g, 1.42 mmol, step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.479 g, 1.71 mmol, Intermediate D), DIPEA (0.75 mL, 4.3 mmol) and 1,4-dioxane (5 mL). The mixture was heated at 100° C. for 12 h and then cooled to room temperature and partitioned between water (50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL) and the combined organic extracts were washed with saturated aqueous NaCl (60 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.655 g) as a light-yellow foam.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccsc21
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of ethyl 6,7-dihydro-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.12 g, 4.2 mmol), sodium hydroxide (6.3 mL, 2 N solution in water, 12.6 mmol) and methanol (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated to remove methanol. The concentrate was diluted with water, cooled to 0° C. and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by vacuum filtration and dried to provide the title compound as an off-white solid (0.81 g, 82% yield). 1H NMR (400 MHz, CDCl3): □ 8.86 (s, 1 H), 7.25 (d, 1 H), 7.16 (d, 1 H), 4.87 (br, 1 H), 1.73 (d, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([F:13])[CH:15]=1)[CH:8]=[CH:7]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1ccc(Cl)c2[nH]ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2ccc3c(OC)ccc(Cl)c32)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
To a solution of 7-chloro-4-(methyloxy)-1H-indole (D11) (1.15 g, 6.35 mmol) in dichloromethane (20 mL) was added 3-fluoro-4-methoxyphenylboronic acid (2.2 g, 12.9 mmol), triethylamine (1.8 mL, 12.9 mmol), copper (II) acetate (2.3 g, 12.7 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Further quantities of 3-fluoro-4-methoxyphenylboronic acid (440 mg), triethylamine (0.36 mL) and copper acetate (440 mg) were added and the mixture stirred at room temperature in the presence of air for a further 16 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was partially purified by silica gel chromatography eluting with 2-35% dichloromethane in hexane. The resulting product was partially dissolved in dimethylsulphoxide and acetonitrile. The undissolved solid was collected by filtration to yield the title compound (D12) (440 mg). The filtrate was concentrated at reduced pressure and the product purified by MDAP to yield a further batch of the title compound (D12), (143 mg).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:22][C:21]([O:40][CH3:41])=[C:20]([O:42][CH3:43])[CH:19]=2)#[N:14].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:36])=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:22][C:21]([O:40][CH3:41])=[C:20]([O:42][CH3:43])[CH:19]=2)#[N:14]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)N4CCOCC4)c4c3OCO4)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.196 g) was added to a mixture of (2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylic acid (0.35 g), morpholine (0.36 ml), N-methylmorpholine (0.112 ml), 1-hydroxybenzotriazole (0.112 ml), DMF (2 ml) and methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 12 hours. The resultant mixture was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.031 g); NMR Spectrum: (DMSOd6) 3.66 (s, 8H), 3.96 (s, 6H), 6.09 (s, 2H), 6.87 (d, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.34 (s, 1H), 7.49 (d, 1H), 7.77 (s, 1H), 8.48 (s, 1H), 9.63 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=[C:24]1[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[C:34]1=[O:39])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=[C:24]1[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH:38][S:12]([C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:34]1=[O:39])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)cc2cnccc21

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:22])[CH3:21]
Reactant: Cc1ccccc1COc1cc(O)cc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2C)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-5-(2-methylbenzyloxy) benzoic acid (20.30 g, 78.6 mM) and acetic anhydride (125 ml, 1.32M) in acetic acid (125 ml) were refluxed for 16 hours. The reaction was cooled and the solvent evaporated ‘in vacuo’. Acetic acid (125 nml) and water (125 ml) were added to the resulting residue and the mixture was stirred for 1 hour at 50° C. Toluene (100 ml) was added and the solvent distilled off ‘in vacuo’ to give 3-acetoxy-5-(2-methylbenzyloxy) benzoic acid as a colourless solid (23.6 g); H1 NMR δ (d6-DMSO) 2.25 (3H s) 2.32 (3H s) 5.12 (2H s) 7.09–7.25 (7H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:27]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]2[I:27])=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(C)c1oc2c(ccc3[nH]ncc32)c(=O)c1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1oc2c(ccc3[nH]nc(I)c32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-2-isopropyl-7H-pyrano[2,3-e]indazol-4-one (20 mg, 0.059 mmol) in dry N,N-dimethylformamide (2 ml) at room temperature are added potassium hydroxide (6.3 mg, 0.112 mmol) and iodine (55 mg, in three portions over 3 h, 0.217 mmol). The reaction mixture is stirred at room temperature for 20 h, then diluted with ethyl acetate and washed successively with 10% aqueous sodium thiosulfate solution (40 ml) and saturated brine (40 ml). The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The resulting solid is triturated with n-hexane/dichloromethane to give a colourless solid that is recovered by filtration and dried.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N,N-Dimethylformamide (100 mL) was cooled to 0° C. and treated with phosphorous oxychloride (5.7 mL, 60.8 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. To this was added 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol) and the resultant solution was stirred overnight Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether and hexanes to give 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (10.6 g, 95%) as a fluffy white solid. 1H NMR (CDCl3): δ 10.07 (s, 1H), 8.37 (d, 1H), 7.78 (m, 2H), 7.48 (t, 1H), 7.20 (m, 3H); 19F NMR (CDCl3) δ−111.25; MS m/z 275 (M+1); Anal. Calcd for C14H8ClFN2O: C, 61.22; H, 2.94; N. 10.20. Found: C, 61.34; H. 2.90; N. 10.15; mp 212–213° C. (decomp.).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])=[CH:22][C:12]3=2)[CH:4]=1.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[ClH:1].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:21]1[C:20](=[O:31])[N:19]([CH3:32])[C:13]2[N:14]([CH3:18])[C:15]3[C:11]([C:12]=2[CH:22]=1)=[CH:10][C:9]([C:5]1[CH:4]=[C:3]([CH2:2][NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:7]([CH3:8])[N:6]=1)=[CH:17][CH:16]=3
Reactant: NCCN1CCOCC1
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CCl
Product: Cl
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CNCCN1CCOCC1

Procedure:
The process is carried out as in Example 122 above, with the compound from Example 122A: 6-(5-chloromethyl-1-methyl-1H-pyrazol-3-yl)-3-(2,4-dichloro-phenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and aminoethyl-morpholine.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].N1CCCCC1.[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[N+:8]([CH2:11][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:25][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:10])=[O:9]
Reactant: SCc1ccccc1
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCCCC1
Solvent: C1CCNCC1
Solvent: CC#N
Product: O=[N+]([O-])CC(SC1CCCCC1)c1ccccc1
Yield: 22.6 %

Procedure:
1.05 ml (10 mmol) of cyclohexanone, 5.5 ml (101 mmol) of nitromethane, 2.1 ml (21 mmol) of piperidine are added to a solution of 5 ml (42 mmol) of benzylmercaptan in 20 ml of acetonitrile. The solution is refluxed for 4 h. At room temperature, the mixture is evaporated and the residue is chromatographed on silica gel (heptane then heptane/ethyl acetate, 50/50, v/v). 600 mg of (1-nitromethyl-cyclohexylsulfanylmethyl)-benzene is obtained in the form of a colorless oil. (Yield=22%).
Reaction SMILES: CC1C=CC(C)=CC=1.[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)[C:16](Cl)=O)(=[O:11])[CH3:10].[Cl:26][CH2:27][C:28]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=C)=[CH:33][CH:32]=1)=[O:29].CN1CCOCC1>[Pd].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][C:28](=[O:29])[CH2:27][Cl:26])=[CH:38][CH:37]=2)[CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(OC(=O)CCl)cc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(C=Cc2ccc(OC(=O)CCl)cc2)cc(OC(C)=O)c1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 69.4 %

Procedure:
A 10 mL round bottom flask was charged with p-xylene (4 mL), Pd II catalyst (4.5 mg, 0.02 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (8.6 mg, 0.02 mmol), 3,5-diacetoxybenzoyl chloride (0.7695 g, 3 mmol), 4-chloroacetoxystyrene (0.393 g, 2 mmol), and N-methyl morpholine (0.276 g, 2.4 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (0.54 g, 69.4%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, 2H, J=8.7 Hz), 7.14-7.10 (m, 4H), 6.99 (q, 2H, J=16.2 Hz), 6.83 (t, 1H, J=2.1 Hz), 4.29 (s, 2H), 2.29 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 169.1, 165.9, 151.4, 150.1, 139.5, 135.1, 129.5, 127.9, 127.7, 121.6, 117.1, 114.7, 41.0, 21.2; HRMS (EI+) found 388.0710 M+, calcd 388.0714 for C20H17ClO6.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[CH:19]=[N:18][N:17](COCC[Si](C)(C)C)[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCCC1.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[NH:1][C:42](=[O:43])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3[nH]c(=O)[nH]c3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (80.0 mg, 0.156 mmol) in tetrahydrofuran (3.0 mL) was treated with N,N-carbonyldiimidazole (50.0 mg, 0.31 mmol) and stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the SEM-protected intermediate which was used without further purification. The crude intermediate was diluted with methylene chloride (4.0 mL) and trifluoroacetic acid (4.0 mL) and stirred at 40° C. for 2 h. The reaction mixture was concentrated, diluted with acetonitrile, adjusted to pH ˜7 with 1 M NaOH, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 13.96 (br s, 1H), 11.03 (br s, 1H), 10.91 (br s, 1H), 7.68 (br s, 1H), 7.22-7.05 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 6.70 (dd, J=8.6, 8.6 Hz, 1H), 6.53-6.39 (m, 1H), 3.46 (s, 3H); LCMS calculated for C20H14F2N5O3 (M+H)+: m/z=410.1. found: 410.1.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:4]1.[CH2:20](N(CC)CC)C.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[ClH:35].[CH2:13]([C:3]1([N:2]([CH3:1])[CH3:19])[CH2:4][CH2:5][CH:6]([N:9]([CH2:10][CH2:11][CH3:12])[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:7][CH2:8]1)[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:20]=1
Reactant: CCCNC1CCC(c2ccccc2)(N(C)C)CC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCN(C(=O)c1ccccc1)C1CCC(Cc2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g of the nonpolar diastereomer of N,N-dimethyl-1-phenyl-N′-propyl-cyclohexane-1,4-diamine (see example 6) were dissolved in 15 ml methylene chloride, and 560 μl triethylamine and approx. 10 mg DMAP were added. 468 μl benzoyl chloride were added dropwise, while cooling in an ice/methanol bath, and the reaction mixture was then stirred overnight, while warming to room temperature. For working up, 12 ml five molar KOH solution and 12 ml water were added, the mixture was stirred for ten minutes and extracted three times with 25 ml methylene chloride each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. From the product obtained (1.31 g), 1.01 g of the nonpolar diastereomer of N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propyl-benzamide hydrochloride were prepared as described for example 1 with water and chlorotrimethylsilane in 2-butanone.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:16]=O>>[CH2:16]1[C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: C=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1

Procedure:
To a mixture of 0.1 NH2SO4 (150 mL) and 37% formaldehyde (80 mL) was added portionwise L-tryptophane (50 g, 245 mmol) with stirring. After being stirred for 4 h at room temperature, the white solid separated out was collected by filtration. The solid cake was washed with water and dried to give 1,2,3,4-tetrahydro-pyrido[3,4-b]indole-3-carboxylic acid, 41 g, (78%); mp 275-276° C. (lit.18 mp 280-282° C.). 1H NMR (DMSO-d6) δ 2.84 (1H, m, CH2), 3.16 (1H, m, CH2), 3.66 (1H, m, CH2), 4.23 (1H, m, CH2), 4.38 (1H, m, CH), 6.98-7.02 (1H, m, ArH), 7.13-7.16 (1H, m, ArH), 7.32-7.34 (1H, m, ArH), 7.45-7.48 (1H, m, ArH), 11.03 (1H, brs, exchangeable, NH).
Reaction SMILES: [CH2:1]([P:3](Cl)[CH2:4][CH3:5])[CH3:2].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Li])=[CH:11][CH:10]=1.IC1C=CC(OC)=CC=1>CCOCC>[CH2:1]([P:3]([CH2:4][CH3:5])[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCP(Cl)CC
Reactant: [Li]c1ccc(OC)cc1
Agent: COc1ccc(I)cc1
Solvent: CCOCC
Product: CCP(CC)c1ccc(OC)cc1
Reaction time: 0.67 h

Procedure:
A solution of 10 g. (0.08 mole) of diethylphosphinous chloride in 100 ml. of ether was added to a solution of p-methoxyphenyllithium [prepared from 23.4 g. (0.1 mole) of p-iodoanisole in 100 ml. of ether and 62.5 ml. of 1.6 M n-butyllithium in hexane] under a nitrogen atmosphere. After 40 minutes, the reaction mixture was filtered and the solvent removed at reduced pressure. Distillation of the residual oil gave (diethyl) (p-methoxyphenyl)phosphine as a colorless liquid, b.p. 85°-90° C. at 0.5 mm.