Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@H:15]([OH:17])[C@:14]([OH:21])([C:18]#[C:19][CH3:20])[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([C:22](O)=[O:23])[CH:6]=[CH:5][C:4]2=1)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][C:56]1[C:61]([CH2:62][NH2:63])=[CH:60][CH:59]=[CH:58][N:57]=1>O1CCCC1>[CH3:55][C:56]1[C:61]([CH2:62][NH:63][C:22]([C:7]2[CH:6]=[CH:5][C:4]3[C@@:3]4([CH2:1][CH3:2])[C@@H:12]([CH2:13][C@@:14]([OH:21])([C:18]#[C:19][CH3:20])[C@@H:15]([OH:17])[CH2:16]4)[CH2:11][CH2:10][C:9]=3[CH:8]=2)=[O:23])=[CH:60][CH:59]=[CH:58][N:57]=1
Reactant: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)O)ccc3[C@]2(CC)C[C@@H]1O
Reactant: Cc1ncccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)NCc4cccnc4C)ccc3[C@]2(CC)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a solution of (6S,7R,4bR,8aR)-4b-ethyl-6,7-dihydroxy-7-prop-1-ynyl-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carboxylic acid (20 mg, 0.061 mmol) in tetrahydrofuran (2 mL) was added sequentially diisopropylethylamine (0.042 mL, 0.24 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (14 mg, 0.073 mmol), 1-hydroxybenzotriazole (9 mg, 0.064 mmol) and C-(2-methylpyridin-3-yl)-methylamine (0.025 mL, approximately 0.2 mmol). The mixture was stirred at room temperature for 1 day and was then quenched with saturated aqueous ammonium chloride solution. After extracting twice with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4) and concentrated under vacuum. The title compound (10 mg, 38%) was isolated by flash chromatography eluting with 50% acetone in methylene chloride. Mass spectrum: m/e 433 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].CS([C:16]1[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[N:17]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][C:16]1[N:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[N:21]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(C(F)(F)F)cc(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 55.8 %

Procedure:
4-Nitro-m-cresol (0.77 g), 2-methanesulfonyl-4,6-bistrifluoromethyl-pyrimidine (1.77 g) and potassium carbonate (1.04 g) were refluxed in acetonitrile (15 ml) for 5 hours. After finishing the reaction, the reaction mixture was poured into ice to separate out crystals. The obtained crystals were filtered and dried to obtain 2-(3-methyl-4-nitrophenoxy)-4,6-bistrifluoromethyl-pyrimidine (1.03 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[C:11](=[O:27])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([CH3:8])[CH2:10][C:11]2=[O:27])[CH3:6]
Reactant: CC1CC(=O)c2cc(NC(=O)c3ccccc3)ccc21
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)c1ccc2c(c1)C(=O)CC2C
Yield: 64.1 %

Procedure:
As presented in the following reaction formula, a solution of bromoethyl acetate (BrCH2COOEt; 7.5 g, 0.045 mol) in acetonitrile (20 mL) was added to a mixture of N-(1-methyl-3-oxo-indan-5-yl)benzamide (10 g, 0.037 mol) and anhydrous potassium carbonate (10.4 g, 0.075 mol) in acetonitrile (150 mL), and the reaction mixture was refluxed for 5 hours. After the completion of reaction, the mixture was filtered and the filtrate was concentrated to give the crude product [benzyl-(1-methyl-3-oxo-indan-5-yl)-amino]-acetic acid ethyl ester (8 g, yield: 63%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([B:25]([OH:30])[OH:26])[CH:12]=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Yield: 78.9 %

Procedure:
According to the method described in example 4.2, starting from 8 g (21.2 mmol) of 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene, 11.1 mL (22.2 mmol) of iPrMgCl and 5 mL (21.6 mmol) of triisopropyl borate, we obtain 4.95 g of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid in the form of oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.CON(C)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:35])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(F)c1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a stirring solution of diisopropylamine (17.69 mL, 0.135 mol) in anhydrous THF (200 mL) at −78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mol), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mol) in anhydrous THF (20 mL). After stirring for 15 min. at −78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mol) in anhydrous THF (10 mL) was added to the reaction mixture which was then stirred for 5 min., and allowed to warm to 0° C. The reaction was quenched with water (400 mL), and extracted with ethyl acetate (3×200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel (1 kg), eluting with 20% ethyl acetate in hexane to give 21.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17]
Reactant: OCc1cccc(F)c1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1cccc(F)c1
Reaction time: 20 h

Procedure:
From 3-fluorobenzyl alcohol (5.1 g; 40 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 20 h at 100° C. The yield was 1.04 g (72%). Mp 115-119° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].CO.I([Cl:28])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Cl:28])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
A solution of 5-acetyl-8-benzyloxycarbostyril (1.75 g, 6 mMol) in 1,2-dichloroethane (60 ml)/methanol (40 ml) and benzyltrimethylammonium dichloroiodate (4.2 g, 12 mMol) was heated at 60° C. under an argon atmosphere for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][N:14]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:17]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=3[N:1]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Nc1cccc(C(=O)O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2,3-Diaminobenzoic acid (1; 200 mg, 1.31 mmol), 6-chloronicotinaldehyde (5; 186 mg, 1.31 mmol), and Na2S2O5 (324 mg, 1.7 mmol) were taken up in DMF (10 mL) and stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with H2O. The resulting mixture was stirred for 1 h at room temperature and filtered. The collected solids were washed with water, MeOH, and dried to afford 2-(6-chloropyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 6 as a pale solid (340 mg, yield: 95%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH3:20])[CH3:19])=[CH:10][C:9]=2[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Rh].C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH3:19])[CH3:20])=[CH:10][C:9]=2[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/COc1cn(C(C)C)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCCOc1cn(C(C)C)c2cc(NC3CCCCC3)c(F)cc2c1=O
Yield: 71.8 %

Procedure:
To an 8.0 ml ethanol solution of 280 mg of ethyl (2E)-4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]oxy}but-2-enoate was added 28 mg of rhodium-carbon (10%) at room temperature, followed by stirring for 2 hours in an atmosphere of hydrogen. After filtration using celite, the filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography to obtain 202 mg of ethyl 4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]oxy}butanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Reactant: COC(=O)CCCCCCCBr
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCC(=O)OC
Yield: 67 %

Procedure:
Using the procedure of example 122, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 8-bromooctanoate giving the title compound, in 67% yield, as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (48 mg, 42%). MS (ISN) 454.9 [(M−H)−]; mp 214–216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][NH:15][CH2:16][CH2:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][CH2:28][C:29]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)OCC[O:30]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][N:15]([CH2:26][CH2:27][CH2:28][C:29]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:30])[CH2:16][CH2:17][CH:18]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC3=CCCN(CCCC(=O)c4ccc(F)cc4)C3)c2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.5 g; 0.0062 mol), potassium carbonate (4.3 g; 0.031 mol), KI (0.06 g; 0.0004 mol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (1.3 ml; 0.0064 mol) in dry dimethylformamide (30 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature, quenched with water and then extracted with diethyl ether. The organic extract was dried (MgSO4) and evaporated under vacuum. The residue was taken up in a solution of hydrochloric acid (37%; 6 ml) in methanol (30 ml). The resulting mixture was stirred for 2 hours at room temperature. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the solvent (methanol) was evaporated under vacuum. The residual alkaline aqueous solution was extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained (1,72 g). A solution of the compound in ethanol was saturated with gaseous hydrogen chloride. A white solid was precipitated. The title compound hydrochloride was collected by filtration, washed with ethanol and dried under vacuum.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[CH2:24]([O:26][C@H:27]1[CH2:44][C@@:43]2([CH3:45])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[C@@H:42]2[C:41](=[O:46])[CH2:40][C@@:38]2([CH3:39])[C@H:34]3[CH2:35][CH2:36][C:37]2=O)[CH2:29][C@@H:28]1[OH:48])[CH3:25]>O1CCCC1>[CH2:24]([O:26][C@H:27]1[CH2:44][C@@:43]2([CH3:45])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[C@@H:42]2[C:41](=[O:46])[CH2:40][C@@:38]2([CH3:39])[C@H:34]3[CH2:35][CH2:36][C:37]2=[CH2:2])[CH2:29][C@@H:28]1[OH:48])[CH3:25]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
Triphenylmethyl phosphonium bromide (7.5 g) was added to a suspension of sodium hydride (500 mg) in dry tetrahydrofuran (100 ml). The mixture was stirred at room temperature for 1.5 hours and then treated with 2β-ethoxy-3α-hydroxy-5α-androstane-11,17-dione (2.43 g). The mixture was refluxed for 1.5 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. Purification of the residue by chromatography over silica in ethyl acetate-petroleum ether (1:2) and crystallization from ether-petroleum ether afforded the titled compound (850 mg), m.p. 103°-108°, [α]D +25.5°.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:24]1
Reactant: CC1CCCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 3-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from isopropyl ether, 3-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1g), melting at 116° C., is obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:12][O:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][C:16]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1)=[O:17]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: COCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COCCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2.5 h

Procedure:
To a solution of 2-trichloroacetyl pyrrole (1.0 equivalent, 4.67 g, 22 mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride (1.0 equivalent, 22 mmol) then aluminium trichloride (1.0 equivalent, 2.93 g, 22 mmol) was added in small portions. After 2.5 hours, the crude mixture was chromatographed on silica gel (MeOH 2% in DCM) to afford 3.0 g of the Friedel-Craft product. 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[I:18]I>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[I:18][C:10]1[C:11](=[O:17])[N:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:9]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Reactant: II
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(I)c(=O)n3n2CCC3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 20, (4.7 g, 19.1 mmol), in carbon tetrachloride/pyridine (140 mL of 1:1 mixture) is added dropwise a solution of iodine in carbon tetrachloride/pyridine (80 mL of 1:1 mixture). After stirring at 0° C. for 30 min, the ice-bath is removed at the mixture was stirred at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into aqueous saturated Na2S2O3. The aqueous phase is extracted with EtOAc (×3). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The resulting yellow solid is purified by silica gel chromatography (5% MeOH/chloroform) to afford 4.2 g of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.97 (d, J=5.1 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H), 2.74 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H); ESI+ MS: m/z (rel intensity) 375.0 (100, M++H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[N:67]1([C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH:71]=[CH:70][CH:69]=[CH:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:76]4[CH:77]=[C:72]([N:67]5[CH:71]=[CH:70][CH:69]=[CH:68]5)[CH:73]=[CH:74][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccc2)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(-n4cccc4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-pyrrol-1-yl-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=441.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: CCCCCCCBr
Product: CCCCCCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 65.7 %

Procedure:
In a similar manner to Exmaple 10(b), by reaction of 2 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde [prepared in Example 16(a)] with 1.1 ml (6.8 mmol) of 1-bromoheptane, 1.88 g (72%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6]2([O:18][CH2:17][CH2:16][O:9]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
4-cyano-4-phenylcyclohexanone (5.97 g, 30 mmole) was taken up in toluene (200 ml) and ethylene glycol (4 ml, 71.6 mmole) was added. After addition of p-toluenesulfonic acid (86 mg, 0.5 mmole) the reaction mixture was heated to the boil in a water separator. The course of the reaction was followed by thin layer chromatography. After 20 hours no starting product could be detected any longer by thin layer chromatography. After cooling, the toluene solution was extracted by shaking with water (5×30 ml) and saturated aqueous NaCl solution (3×20 ml) and dried over Na2SO4. After removing the solvent on a rotary evaporator the desired ketal was obtained in a yield of 6.8 g (94%) as a white solid with a melting point of 108°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21](Cl)(=[O:23])=[O:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N3CCOCC3)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (1 g) in DCM is added to a solution of morpholine (2.26 mL) in water (50 mL) and stirred at rt for 5 h. The organic phase is separated and washed water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole (1.3 g, 100%). MS: 439 (M+H).