Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:18])[CH2:8][NH:7][CH2:6][CH:5]1[C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=1)[CH3:3].CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:37])[O:33][C@H:32]([C:34](Cl)=[O:35])[CH2:31][O:30]1>C(Cl)Cl>[CH3:28][C:29]1([CH3:37])[O:33][C@@H:32]([C:34]([N:7]2[CH2:6][C@@H:5]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=3)[C@@:4]([C@H:2]([OH:1])[CH3:3])([CH3:18])[CH2:8]2)=[O:35])[CH2:31][O:30]1
Reactant: COc1ccc(C2CNCC2(C)C(C)O)cc1O
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc([C@@H]2CN(C(=O)[C@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask equipped with a stir bar and rubber septum was charged with 5-[4-(1-hydroxy-ethyl)-4-methylpyrrolidin-3-yl)-2-methoxyphenol (2.4 g, 9.55 mmol), dry CH2Cl2 (50 mls), and DIEA (3.49 mls, 20.1 mmol) under a nitrogen atmosphere. The mixture was chilled to 0° C. and (S)-2.2-dimethyl-[1,3]dioxolane-4-carbonyl chloride (3.14 g, 19.1 mmol) in 15 ml of CH2Cl2 was added dropwise by syringe. The reaction mixture was allowed to gradually warm to room temperature over a 16-hour period. The mixture then was diluted with 50 ml of CH2Cl2, washed with 1N HCl (2×50 ml), saturated aqueous NaHCO3 (1×50 ml), dried over Na2SO4, and concentrated to 3.9 g of a tan foam. The material was taken up in 100 ml CH3OH and chilled to 0° C. Three equivalents of aqueous 1N LiOH then were added (29 ml, 29.0 mmol), the mixture was stirred at 0° C. for 2 hours, then warmed to room temperature for 2 hours. The reaction mixture next was concentrated under reduced pressure with the bath temperature at 30° C. to remove CH3OH. The remaining aqueous material was neutralized with saturated NH4Cl to pH 7 and extracted with EtOAc (2×100 ml). The extracts were dried over Na2SO4 and concentrated to 2.74 g of a tan foam (76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: OC1CCOC1
Product: N#Cc1cnc(N)cc1OC1CCOC1

Procedure:
From intermediate 16 and racemic tetrahydrofuran-3-ol, reacted in an analogous manner to the preparation of intermediate 20. (UPLC-MS 3) tR 0.48 min, ESI-MS 206.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.Br[CH2:11][C:12]1[C:13]([Cl:22])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.C(N(CC)CC)C>C(O)C>[Cl:22][C:13]1[C:12]([CH2:11][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Clc1nc2ccccc2cc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of 6-methyl-2-sulfanylpyrimidin-4-ol (0.492 g, 3.46 mmol) and 3-(bromomethyl)-2-chloroquinoline (1.27 g, 4.95 mmol) in anhydrous ethanol (30 mL) at room temperature was added triethylamine (1.50 g, 14.85 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and water (50 mL) was added. The mixture was sonicated, and a white solid precipitated out. The product was filtered, washed with water, washed with ether, and then dried in vacuo to provide 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (1.03 g, 66% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 4.57 (s, 2H), 6.00 (bs, 1H), 7.61 (t, 1H), 7.78 (t, 1H), 7.79 (d, J=10.8 Hz, 1H), 8.01 (d, J=10.8 Hz, 1H), 8.67 (s, 1H); M+ 317.8.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:9][CH:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[O:12])[CH2:6][CH2:7][CH3:8]>C(O)CCC>[C:1]([C:2]([CH:11]([OH:12])[CH:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH2:3])#[N:4]
Reactant: C=CC#N
Reactant: CCCCOC(C=O)OCCCC
Solvent: CCCCO
Product: C=C(C#N)C(O)C(OCCCC)OCCCC

Procedure:
0.17 mole acrylonitrile and 30 g (0.15 mole) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1to form 22 g of 2-cyano-4,4-dibutoxy-3-hydroxy-1-butene which distilled at 108° C. under 0.1 mbar.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1>[Ni].C(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH2:13][CH:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CCOc1cccc2oc(-c3nnn[nH]3)cc(=O)c12
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCOc1cccc2c1C(=O)CC(c1nnn[nH]1)O2
Reaction time: 8 h

Procedure:
To a solution of 1 part of 5-[5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole in 50 parts of ethanol was added 5 parts of Raney nickel catalyst. The resulting mixture was hydrogenated at 20°C and 45 lbs/sq. in. pressure for 8 hours. The catalyst was filtered off and the filtrate was evaporated to give an oil which solidified on trituration with petroleum ether (b.p. 40°-60°C). This solid was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60°C) to give 0.2 parts of 5-[2,3-dihydro-5-(3-methylbutoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole as a white solid, m.p. 134°-137°C. The structure of this product was confirmed by n.m.r. and m.s. measurements.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1ccc2c(Cc3ccc(N)cc3)ccnc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (0.187 g, 0.603 mmol) and tin(II) chloride dihydrate (0.823 g, 3.62 mmol) in MeOH (10 mL) was heated to 60° C. After 1 hr, an additional 5 eq of tin(II) chloride dihydrate was added. After 3 hrs, the mixture was concentrated in vacuo and diluted with EtOAc and water. Saturated NaHCO3 was added until the aqueous layer was basic. The resulting suspension was filtered and the solids washed with EtOAc. The organic fraction was washed with water and brine. After drying with Na2SO4 and concentrating in vacuo, the crude yellow solid, 4-((7-methoxyquinolin-4-yl)methyl)benzenamine was advanced without further purification. MH+=265.1@0.99 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17](OC)=O)[CH:15]=[CH:16][C:3]1=2.[NH3:21]>CO>[C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: N
Solvent: CO
Product: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir 5 gm. of methyl 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylate in 500 ml. of methanol saturated with ammonia gas for 24 hours at room temperature. Evaporate the reaction mixture to dryness. Reflux the residue in 200 ml. of methylene chloride containing 10 gm. of phosphorous oxychloride for eight hours. Cool the reaction mixture to room temperature and shake several times with water. Separate the organic layer, dry over magnesium sulfate and evaporate to dryness to obtain the title product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][N:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:25]4[C:26](=[O:28])[CH2:27][N:23]([CH3:22])[C:24]4=[O:29])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: CN1CC(=O)NC1=O
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CC(=O)N(Cc2ccc3c(-c4ccc(F)cc4)cc(C#N)nc3c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 50.0 mg, 0.147 mmol, 1.0 equiv.), 1-methylimidazolidine-2,4-dione (18.4 mg, 0.161 mmol, 1.1 equiv.) and cesium carbonate (95.0 mg, 0.293 mmol, 2.0 equiv.) were combined into 1.0 ml of DMF. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was filtered and the filtrate was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile (2-2, 48.0 mg, 87.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.205 (d, J=1.09 Hz, 1H); 7.941 (d, J=8.79 Hz, 1H); 7.681 (dd, J1=8.79 Hz, JZ=1.83 Hz, 1H); 7.647 (s, 1H); 7.454-7.503 (m, 2H); 7.251-7.309 (m, 2H); 4.935 (s, 2H); 4.049 (s, 2H); 3.057 (s, 3H). LRMS m/z (M+H)+ 375.1 found, 375.1 required.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8](SC)[CH2:7][C:6]=2[CH:23]=1.[C:26]([NH:31][NH2:32])(=O)[CH2:27][CH2:28][CH3:29]>CN(C=O)C.Cl>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]3[C:26]([CH2:27][CH2:28][CH3:29])=[N:31][N:32]=[C:8]3[CH2:7][C:6]=2[CH:23]=1
Reactant: COc1cc2c(cc1Br)CC(SC)=NN=C2c1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)NN
Agent: Cl
Solvent: CN(C)C=O
Product: CCCc1nnc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc(OC)c(Br)cc1C2
Temperature: 112.5 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
1.17 g (2.78 mmol) of the compound of step B is dissolved in 40 ml of anhydrous DMF and mixed with 0.73 g (8.4 mmol) of butyric acid hydrazide as well as 3 drops of concentrated HCl. The mixture is stirred for 5 hours at 110-115° C. Then, the mixture is poured onto ice (160 g) and stirred for 1 more hour. The precipitated crystals are suctioned off and washed with water. 1.05 g (83%) of 9-bromo-6-(4-nitrophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo(4,3-c][2,3]benzodiazepine with a melting point of 238-240° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].CN(C)C=O.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]#[N:11]
Reactant: N#CCc1ccc(Br)cc1Br
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCC(C#N)c1ccc(Br)cc1Br
Reaction time: 2 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 27.5 parts of 2,4-dibromobenzeneacetonitrile, 135 parts of N,N-dimethylformamide and 67.5 parts of benzene are added portionwise 3.2 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. After stirring for one hour, 14 parts of 1-bromobutane are added dropwise. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is distilled, yielding 22 parts of 2,4-dibromo-α-butylbenzeneacetonitrile; bp. 124° C. at 0.05 mm. pressure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[N:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=3)[N:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)c1ccc2nc(CCl)ccc2c1
Reactant: C1CCNC1
Solvent: CCO
Product: FC(F)(F)c1ccc2nc(CN3CCCC3)ccc2c1

Procedure:
2-(Pyrrolidin-1-ylmethyl)-6-trifluoro-methylquinoline may be prepared by carrying out the procedure as in Example 29, but starting with 3 g of -2-chloromethyl-6-trifluoromethylquinoline and 2.6 g of pyrrolidine in 30 ml of ethanol. The crude product obtained is chromatographed on a silica gel column, eluting with a mixture of dichloromethane and methanol (99-1 by volume). 2.5 g of 2-(pyrrolidin-1-ylmethyl)-6-trifluoromethylquinoline are thus obtained in the form of an orange-coloured oil [1H NMR spectrum in CDCl31 T=300K, δ in ppm (300 MHz) : 2.15 (4H, m, 2 CH2), 3.30 (4H, m, 2 NCH2), 4.50 (2H, s, NCH2), 7.90 (1H, d, J=8 Hz, arom. CH), 8.15 (2H, m, 2 arom. CH), 8.25 (1H, d, J=8 Hz, arom. CH), 8.35 (1H, d, J=8 Hz, arom. CH)].
Reaction SMILES: [CH:1]1[C:14]2[C:13]([CH2:19][C:20](O)=[O:21])([CH2:15][C:16]([OH:18])=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O>C(OC(=O)C)(=O)C>[O:17]1[C:20](=[O:21])[CH2:19][C:13]2([C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:15][C:16]1=[O:18]
Reactant: O=C(O)CC1(CC(=O)O)c2ccccc2Oc2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1CC2(CC(=O)O1)c1ccccc1Oc1ccccc12

Procedure:
A solution of xanthene 9,9-diacetic acid (0.8 g.) in acetic anhydride (3 ml.) is heated under reflux for 1 hour, cooled and poured into water. Extraction with ethyl acetate gives xanthene-9-spiro-4'-tetrahydropyran-2',6'-dione which is recrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.), m.p. 188°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:42][C:43]1[N:48]=[C:47]([NH2:49])[CH:46]=[CH:45][N:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:49][C:47]5[CH:46]=[CH:45][N:44]=[C:43]([CH3:42])[N:48]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Cc1nccc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccnc(C)n3)ccc12
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
A vial was charged with perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE KKKKK; 64.75 mg, 0.109 mmol), 2-methylpyrimidin-4-amine (12.50 mg, 0.115 mmol), and THF (546 μl) (not all the amine dissolved). The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (229 μl, 0.229 mmol) was added. After 40 min, the mixture was loaded directly onto a silica gel loading column. The column was eluted onto a pre-equilibrated 12-g Redi-Sep Gold column with 0-5% MeOH/DCM to give 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(2-methylpyrimidin-4-yl)isoquinoline-6-sulfonamide (28.4 mg, 0.055 mmol, 50.2% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.32 (br. s., 1H), 8.68 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.17-8.03 (m, 2H), 7.95 (dd, J=1.7, 8.9 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.68-7.59 (m, 2H), 7.56-7.48 (m, 2H), 7.46-7.39 (m, 1H), 7.29 (tt, J=2.2, 9.3 Hz, 1H), 6.90 (br. s., 1H), 3.77 (s, 3H), 2.35 (s, 3H). m/z (ESI) 519.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:19]1[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]1)=[O:15]
Reactant: CC1CNCC(C)C1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: CC1CC(C)CN(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.1 mg). Calcd for C17H19ClN2O2: 318.1135, found 318.1136.
Reaction SMILES: [CH2:1]([N:8]([CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:13]=2[CH2:12]1)[CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](O)=[O:24]>>[CH2:1]([N:8]([CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][CH:23]=[O:24])=[CH:21][C:13]=2[CH2:12]1)[CH:9]=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1ccc2c(c1)CC(N(C=O)Cc1ccccc1)CCC2
Product: O=CNc1ccc2c(c1)CC(N(C=O)Cc1ccccc1)CCC2

Procedure:
A solution of N-benzyl-N-formyl-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.80 g) in formic acid (16 ml) was refluxed for 2 hours. After cooling, the solution was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed successively with 1N sodium hydroxide solution, 1N hydrochloric acid, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give N-benzyl-N-formyl-(3-formylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.84 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]3)[N:10]=2)[C:5]([O:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[CH3:29])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(Cl)cnc3F)n2)c1C(F)(F)F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ncc(Cl)cc1-c1cccc(-n2ncc(C(=O)O)c2C(F)(F)F)n1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 239 Step A with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 632.7 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ 8.22 (m, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.83 (m, 3H), 7.63 (m, 2H), 5.70 (s, 2H), 2.52 (s, 3H).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH:7]([C:9]#[N:10])[CH3:8])(=[O:5])[OH:4])[CH3:2].[CH2:11](O)[CH2:12][CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH:7]([C:9]#[N:10])[CH3:8])(=[O:4])[O:5][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:2]
Reactant: OCCCCO
Reactant: CCP(=O)(O)CC(C)C#N
Solvent: Cc1ccccc1
Product: CCP(=O)(CC(C)C#N)OCCCCO
Reaction time: 4 h
Yield: 91.9 %

Procedure:
540 g (3.0 mol) of ethyl(2-cyano-2-methylethyl)phosphinic acid (produced as in Example 6) are at 80° C. dissolved in 400 ml of toluene and admixed with 315 g (3.5 mol) of 1,4-butanediol and esterified at about 100° C. during 4 h in a distillation apparatus equipped with a water trap. After the esterification has ended, the toluene is separated off in vacuo to leave 643 g (92% of theory) of 4-hydroxybutyl ethyl(2-cyano-2-methylethyl)phosphinate as colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])[CH3:2].S(=O)(=O)(O)[OH:22]>>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6](=[O:22])[CH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])[CH3:20]
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CC#CCCC(C)c1cccc(OC)c1
Product: CCN(CC)CCC(=O)CCC(C)c1cccc(OC)c1

Procedure:
Dissolve 1-diethylamino-6-(m-methoxyphenyl)hept-2-yne (13.6 g) in 10% aqueous sulphuric acid (40 cc) and stir with mercuric sulphate (0.69 g) for 2 hours at 70°. Filter the cooled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and brine, and dry (Na2SO4). Evaporate the solvent and distil the residue to obtain 1-diethylamino-6-(m-methoxyphenyl)heptan-3-one which has partially eliminated to 6-(m-methoxyphenyl)hept-1-en-3-one during the distillation, b.p. 145°/12 mm Hg.
Reaction SMILES: [Na+].[CH3:2][C:3]([C:11]1[CH:12]=[C:13]([S:17]([O-:20])(=O)=[O:18])[CH:14]=[CH:15][CH:16]=1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:23])=O.C>CN(C=O)C.CCCCCC>[CH3:2][C:3]([C:11]1[CH:12]=[C:13]([S:17]([Cl:23])(=[O:20])=[O:18])[CH:14]=[CH:15][CH:16]=1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)[O-])c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
3-(α,α-Dimethylbenzyl)benzenesulphonic acid sodium salt (9.6 g) is dissolved in DMF (16 ml) and cooled to 10° C. Thionyl chloride (12ml) is added dropwise maintaining the temperature below 20° C. The mixture is allowed to warm to room temperature and stirred one hour. The solution is poured onto ice/water (100 ml) and the mixture is extracted with ether (3×8 ml). The combined extracts are dried (MgSO4) and the solvent evaporated to give pale yellow waxy crystals which are dissolved in hexane (200 ml) and decolourised (charcoal). Evaporation produces white crystals of 3-(α,α-dimethylbenzyl)benzenesulphonyl chloride which are dried at room temperature under vacuum, m.p. 47.5°-49° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:13]2[C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]1[CH3:19].N#N.[CH3:22]I>CS(C)=O.O1CCCC1>[CH3:3][N:4]1[C:13]2[C:12](=[O:14])[N:11]([CH3:22])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]1[CH3:19]
Reactant: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2
Reactant: CI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(n1C)C(=O)N(C)c1ccccc1N2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.33 g (0.011 mole) of 80% sodium hydride (in paraffin) are added to a cold solution (5° C.) of 2.3 g (0.01 mole) of 1,2-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one in 20 ml of dry dimethylsulfoxide and 20 ml of tetrahydrofuran under an inert gas atmosphere (N2). The mixture is stirred for 30 minutes and is allowed to come to room temperature (30 minutes). Thereafter, it is again cooled to 5° C. and 1.4 g (0.01 mole) of methyl iodide, dissolved in 5 ml of dry tetrahydrofuran, are added dropwise. After the mixture has been stirred at 35° C. for 2 hours, 50 ml of ice-water are added, and the mixture is extracted several times with ethyl acetate. The combined extracts are concentrated in vacuo, and the residue is chromatographed on neutral silica gel (methylene chloride/methanol), yield: 1.7 g.
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1>[Fe].C(O)(=O)C>[CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1

Procedure:
The title compound was prepared according to the procedure described in General Method B, using methyl-(1-methyl-piperidin-4-yl)-(5-nitro-benzooxazol-2-yl)-amine (0.583 g, 2.01 mmol), acetic acid (8 mL), and iron (1.12 g, 20.1 mmol) to provide product (0.474 g, 91%). mass spectrum (m/e): 261.2 (M+1).