Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[N:19]([CH3:34])[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)[CH:22]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])C.[Li+].[OH-]>>[CH3:34][N:19]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[C:15]3[C:10]([CH:9]=[CH:8][N:7]3[CH:5]([CH3:6])[C:4]([OH:35])=[O:3])=[CH:11][CH:12]=2)=[CH:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=2)=[N:20]1
Reactant: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)O)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-{6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-{6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid as off-white crystals.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:39][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)#[N:29]
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-cyanobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (21%); 1H NMR (d6-DMSO) δ 8.09–8.03 (m, 4H), 7.94 (d, J=8.0 Hz, 1H), 7.40–7.07 (m, 12H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 519 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 9 %

Procedure:
10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 4.4 mg (9%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=424.0.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](O)[CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:27][N:26]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(OC1C=CC(C2C=CC(C)=CN=2)=CC=1)CCCCCCC.[Li+].CC([N-]C(C)C)C.O1C(CCOCCC)C1>C(Cl)Cl>[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([F:7])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:27][N:26]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCC(O)CCOCCC)cn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: CCCCCCCCOc1ccc(-c2ccc(C)cn2)cc1
Agent: CCCOCCC1CO1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(CCC(F)CCOCCC)cn2)cc1
Reaction time: 12 h

Procedure:
0.11 mol of DAST is added at -30° C. to a solution of 0.1 mol of 2-(p-octyloxyphenyl)-5-(3-hydroxy-6-oxanonyl)pyridine (obtainable by reaction of 2-(p-octyloxyphenyl)-5-methylpyridine with LDA at -40° C. and optically active 1,2-epoxy-5-oxaoctane) in methylene chloride, and the reaction mixture is then warmed slowly to room temperature. After 12 hours, the mixture is subjected to customary work-up, and the product is purified by crystallization, to give optically active 2-(p-octyloxyphenyl)-5-(3-fluoro-6-oxanonyl)pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:1]3[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]3)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COc1cc(CO)ccc1Cn1cccn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc(Cn3cccn3)c(OC)c2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of Ethyl 1H-pyrazole-4-carboxylate (117 mg, 0.833 mmol), crude (4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)methanol (256 mg, 71%, 0.833 mmol) and Triphenylphosphine (328 mg, 1.249 mmol) in THF (8 ml) DEAD 40% in Toluene (0.494 ml, 1.249 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 2 h and continued to stir for 12 h at rt. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Ethyl 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylate. MS [M+H]+=341.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH:33]1[CH2:42][NH2:43].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:19])[CH2:18][NH:43][CH2:42][CH:33]2[CH2:34][CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32]2)=[CH:11][C:10]=1[NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNCC2CCc3ccccc3C2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 770 mg of 4-benzyloxy-3-(N-tert-butoxycarbonyl-N-methylsulfonylamino)-1-((2S)2,3-epoxypropoxy)benzene (1.71 mmol) and 300 mg (1.8 mmol) of 1,2,3,4-tetrahydronaphthalen-2-ylmethylamine, obtained as described in EP-A-436435, in 20 ml of absolute ethanol is heated under reflux for 16 hours. The mixture is cooled, 3 ml of an ethanol solution saturated with hydrochloric acid are added thereto and the medium is heated at 50° C. for 5 hours. The solvent is evaporated and the medium is taken up with a mixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a silica gel column, eluting with a methylene chloride/methanol=95/5 mixture. The title compound is obtained in the form of a glassy solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11])#[N:13]
Reactant: Cc1ncsc1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: CNC(=NCCSCc1scnc1C)NC#N

Procedure:
A solution of 19.7 g. of 5-(2-aminoethyl)thiomethyl-4-methylthiazole and 11.2 g. of N-cyano-N', S-dimethylisothiourea in 500 ml. of acetonitrile is refluxed for 24 hours. The mixture is concentrated and the residue is chromatographed on a column of silica gel to give N-cyano-N'-methyl-N"-[2-(4-methyl-5-thiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1)=[O:2].[BH4-].[K+].P([O-])(O)(O)=O.[Na+]>O1CCCC1.O>[OH:2][CH2:1][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)o1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CO)o1
Reaction time: 5 h
Yield: 87.1 %

Procedure:
0.87 g of the aldehyde of Stage A in 5 ml of tetrahydrofuran and 1 ml of water was cooled to 0° C. and 0.47 g of potassium borohydride were introduced. The mixture was stirred for 5 hours, poured into an aqueous sodium dihydrogenphosphate solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 0.77 g of the expected product.
Reaction SMILES: C[Si](C)(C)C#CCP(=O)(OCC)OCC.[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[CH:33])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[C:33][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: Ic1ccccc1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: CCOP(=O)(CC#C[Si](C)(C)C)OCC
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2ccccc2)CC1

Procedure:
The title compound was obtained as described for the Compound of Example 1, reacting Compound 1c with iodobenzene instead of 2-bromo-6-methylpyridine. Purification by flash chromatography with Petroleum Ether-EtOAc 65:35 afforded the title product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:12])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)N1CCCCC1)c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 54.7 %

Procedure:
To a solution of 15 g of β-p-fluorobenzoyl-propionic acid and 8.0 g of triethylamine in 100 ml of tetrahydrofuran, was gradually added 8.3 g of ethyl chlorocarbonate while the reaction mixture was kept below 0°C. After being stirred for 25 minutes at a temperature below 0°C, the mixture was added with 6.5 g of piperidine and stirred for another 2 hours. Then the precipitate formed was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from hexane to obtain 11 g of 1-(β-p-fluorobenzoylpropionyl)piperidine, melting at 70° - 71°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a stirred solution of ethyl (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetate (3 g, 10.22 mmol) in ethanol (30 ml) was added 1N sodium hydroxide solution (30 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The residue obtained after the evaporation of the solvent under reduced pressure was acidified with 1N HCl. The desired product was extracted into ethyl acetate (3×50 ml), washed with water (100 ml), brine, dried (Na2SO4) and concentrated to give 2.6 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 3.96 (s, 2H), 6.36 (s, 1H), 6.80 (d, J=8.1 Hz, 1H), 7.22 (d, J=9.3 Hz, 1H), 7.51 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([OH:15])=O)=[O:7])=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH2:56])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH:56][C:13](=[O:15])[CH2:12][S:11][CH2:10][CH2:9][NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)CSCCNC(=O)c1ccoc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccoc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
There was suspended 3.52 g (0.0154 mol) of 2-[(3-furoylamino)ethylthio]acetic acid in 80 ml of dichloromethane and added 2.36 g (0.0154 mol) of HOBt and 3.17 g (0.0154 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 4.0 g (0.0138 mol) of 4-[3-(piperidino-methyl)phenoxy]-cis-2-butenylamine, and the mixture was stirred for 12 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 10% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 2.9 g of the titled compound as oily matter.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C=CC(C(OCC2C=CC=CC=2)=O)=CC=1>>[CH3:33][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][CH:32]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Benzyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate-Using benzyl 4-hydroxybenzoate, the title compound was synthesized as a white, crystalline solid. PMR (CDCl3): δ 1.32 (6H, s), 1.35 (6H, s), 1.72 (4H, s), 5.38 (2H, s), 7.24-7.48 (8H, m), 7.92 (1H, dd, J~8.8 Hz, 1.8 Hz), 8.12-8.20 (3H, m).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH:8]2[C:20]#[N:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH:8]2[CH2:20][NH2:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1CN(Cc2ccccc2)CCN1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CN(Cc2ccccc2)CCN1c1ccccc1

Procedure:
In a manner similar to Preparation 2, react 1-phenyl-4-(phenylmethyl)-2-piperazinecarbonitrile (16.6 g, 60 mmol) with lithium aluminum hydride (6.8 g, 180 mmol) to obtain the title compound.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>C1COCC1>[CH:18]1([CH2:17][C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:16][CH2:15]1
Reactant: CC(C)C#N
Reactant: BrCC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)CC1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of isobutyronitrile (29 mmol) in THF (60 mL) is added LDA (2 M in THF, 35 mmol) at −78° C. After stirring at −78° C. for 2 h, to this solution is added bromomethyl cyclopropane (32 mmol) at −78° C. The mixture is stirred at room temperature for 13 h, and then the reaction is quenched by the addition of aq. NH4Cl. The mixture is extracted with ether, and the combined organic extracts are washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 3-cyclopropyl-2,2-dimethylpropionitrile, which is directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>CCO.C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CCc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Yield: 85.1 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (1.85 g, 4.16 mmol) was hydrogenated using Ra—Ni (1 g) in EtOH/THF (50 mL) for 1.4 h. The reaction was filtered and concentrated to give a solid. Recrystallization from hot CH3CN gave the title compound as a white solid (1.58 g, 3.54 mmol, 85%). MS: APCI: M+1: 447.1 (Exact Mass: 446.16).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCNCC2)CC1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(Br)cc2C2CCC(C)(C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a mixture of the crude product of 1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine produced in Example (57a) (1.21 g), butyraldehyde (0.35 mL, 3.98 mmol), acetic acid (0.1 mL, 3.32 mmol) and tetrahydrofuran (8 mL) was added sodium triacetoxyborohydride (1.1 g, 4.98 mmol), followed by stirring for 2 hours and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 901 mg of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:19][CH2:20][O-:21].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([O:21][CH2:20][CH3:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COc1cc(Br)cc2[nH]c3c(Cl)nc(Cl)nc3c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)cc(OC)c12
Temperature: 25 °C
Yield: 74.2 %

Procedure:
600 mg (1.7 mmol) 7-bromo-2,4-dichloro-9-methoxy-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 174 mg (2.6 mmol) sodium ethylate. The mixture was refluxed for 3 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 450 mg (73%) 7-bromo-2-chloro-4-ethoxy-9-methoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 354, 356 [M−H]−
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([OH:9])=[O:8]
Reactant: O=C([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1

Procedure:
First, 1,3,4,5,6-pentamethyl-Dewar benzene-2-carboxylic acid was synthesized. Ethyl 1,3,4,5,6-pentamethyl Dewar benzoate (5.0 g) was combined with 3.80 g of potassium hydroxide in 50 mL methanol. This solution was stirred at gentle reflux for 16 hours. All methanol was then removed by rotary evaporation, and the resulting residue was dissolved in 75 mL water. To this solution was added 10% HCl (aq) dropwise until the pH of the solution was acidic. The resulting white precipitate was collected by vacuum filtration and dried in a vacuum desiccator overnight to yield 3.70 g of dry white solid (85% yield). The product was analyzed by 1H NMR (CDCl3) δ 2.04 (s, 3H); 1.62 (m, 3H); 1.58 (m, 3H); 1.24 (s, 3H); 1.16 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[Br:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][C:17](=[S:37])[NH:18][C:19]1[S:29][C:22]2[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]=2[C:20]=1[C:30]([O:32]C(C)(C)C)=[O:31])=[O:15]>>[Br:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][C:17](=[S:37])[NH:18][C:19]1[S:29][C:22]2[CH2:23][O:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21]=2[C:20]=1[C:30]([OH:32])=[O:31])=[O:15]
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2Br)sc2c1CC(C)(C)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccccc3Br)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of 40% v/v TFA/DCM (13.4 mL) was added to tert-butyl 2-(3-(2-bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.25 g, 0.48 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(2-Bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.16 g, 0.33 mmol, 69% yield) was isolated as a pale, yellow solid. 1H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 13.48 (s, 1H), 12.21 (s, 1H), 7.72 (apparent dd, J=7.8, 1.2 Hz, 1H), 7.62 (apparent dd, J=7.4, 1.8 Hz, 1H), 7.53-7.42 (m, 2H), 4.66 (s, 2H), 2.75 (s, 2H), 1.23 (s, 6H). 13C NMR (101 MHz, DMSO) δ 174.29, 167.42, 165.95, 147.16, 137.00, 133.01, 132.56, 129.70, 129.60, 128.04, 124.63, 119.33, 116.98, 70.62, 59.29, 37.74, 26.65. LCMS retention time: 3.193 min; LCMS purity at 214 nm=98%. HRMS m/z calculated for C18H18BrN2O4S2 [M++1]: 468.9886. found 468.9860. Melting point 188.4° C., decomposition.
Reaction SMILES: [OH-].[K+].[OH:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7]>O.CO>[OH:3][C@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([OH:8])=[O:7]
Reactant: C=C(C(=O)OC)C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C(=O)O)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of potassium hydroxide (2.65 g, 0.047 mol, 1.3 eq) in water (60 mL) was added drop wise to a solution of 1b (7 g, 0.036 mol, 1 eq) in methanol (20 mL) (see FIG. 5). The mixture was stirred at room temperature for 15 h. The solution was then concentrated under vacuum. The aqueous phase was washed with ether (2×100 mL), acidified with 6N aqueous HCl solution and extracted with ether (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil which crystallized upon standing. The desired product 9b was obtained as a solid (6.29 g, 97%). Rf 0.26 (hexane/EtOAc=6:4). 1H NMR δ (DMSO-d6) 5.41 (s, 1H), 5.61 (s, 1H), 5.93 (s, 1H), 6.15 (s, 1H), 7.22 (m, 5H), 12.45 (s, 1H). [M−H]− 177.1, tR=1.23 min; purity: 91%.