Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7](C(OCC)=O)[C:6](=[O:13])[CH2:5][CH2:4][N:3]1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(O)=O>[N:3]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][C:2]1=[O:1]
Reactant: CCOC(=O)C1C(=O)CCN(N2CCCCC2)C1=O
Solvent: CC(=O)O
Product: O=C1CCN(N2CCCCC2)C(=O)C1
Temperature: 125 °C
Yield: 22 %

Procedure:
Ethyl 2,4-dioxo-1,1′-bipiperidine-3-carboxylate (11.36 g, 42.38 mmol, Example 14) was dissolved in 10% AcOH (200 mL) and heated at reflux 125° C. for 1 h. The cooled reaction was evaporated, and the residue was purified by flash chromatography using a gradient of 9:1 to 1:1 CH2Cl2/acetone, to give the product as a yellow viscous oil (6.4 g, 22% yield for the two last steps).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]([CH3:18])[CH3:17].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)CN(c1ccc(I)cc1)c1ncccn1
Yield: 93.6 %

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (150 mg) and isobutyl bromide (83 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-isobutylpyrimidin-2-amine (167 mg).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:18][CH:17]([C:19](O)=[O:20])[CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH3:41][N:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:19]([CH:17]1[CH2:16][C:6]2[C:7]3[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[CH2:18]1)=[O:20]
Reactant: O=C(O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CNc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A solution of 6-nitro-2,3,-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxaline-8-carboxylic acid (1 mmol, example 78) in anhydrous DMF was treated with carbonyldiimidazole (2 mmol) and triethylamine (1 mL) and then heated at 70° C. for 45 min. After cooling to room temperature methylphenylamine (1.2 mL) was added and the mixture stirred at 50° C. for 6 h. The solvent was removed in vacuo, and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C19H16N4O5.1.2 H2O: C, 56.77; H, 4.61; N, 13.93; found: C, 56.22; H, 4.13; N, 14.62. MS M+1 (381).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [K+]
Product: COc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similat to that of Procedures 3 and 4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nn1
Yield: 33 %

Procedure:
tert-Butyl 5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.42 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (57 mg, 33%) as an orange solid: mp 310-315° C.; 1H NMR (500 MHz, CD3OD) δ 8.47 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.25 (dd, J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.9 Hz, 1H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.2 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 372 [M+H]+; HPLC (Method B) 98% (AUC), tR=9.3 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(C(F)(F)F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-(trifluoromethyl)benzene (Aldrich, 85 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.57 (s, 1H), 7.71-7.96 (m, 2H), 8.09-8.32 (m, 3H), 8.62 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 309 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][NH:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].C(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[S:15][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:4]=1
Reactant: CCOC(=O)C(=O)NCC(=O)OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc(OC)s1
Temperature: 60 °C
Reaction time: 7 h
Yield: 7.4 %

Procedure:
A mixture of ethyl 2-(2-methoxy-2-oxoethylamino)-2-oxoacetate (1.00 g, 5.29 mmol) and phosphorus pentasulfide (1.29 g, 5.82 mmol) in chloroform (20 ml) was stirred at 60° C. for 7 h. To the cooled reaction mixture DCM (100 ml) was added and the mixture was washed with water (50 ml) and brine (50 ml). Organic phase was dried over Na2SO4 and evaporated. Evaporation residual was dissolved in dry MeCN (10 ml) and phosphorus pentoxide (0.75 g, 5.29 mml) was added and the mixture was heated to reflux for 4.5 h. To the cooled reaction mixture water (35 ml) was added and the mixture was extracted with EtOAc (3×50 ml). Combined organic fractions were dried over Na2SO4 and evaporated to give crude product, which was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: C-18, eluent: 0-100% MeCN in water) to yield 73 mg (7%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.42 (t, 3H), 4.01 (s, 3H), 4.43 (q, 2H), 7.30 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.[OH-].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1([OH:18])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Product: CN1CCC(O)(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-bromoindole (490 g), 1-methyl-4-piperidone (339 mL) and potassium hydroxide (15 g) in IMS (3L) was stirred under nitrogen at room temperature for 24 hrs. The mixture was cooled to 7° and filtered. The filter cake was washed with ethanol (300 mL) followed by water (800 mL) to give an off-white powder which was dried in vacuo at 50° for 24 hr (563.8 g, 73% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 2-hydroxy-4-nitrobenzonitrile (0.5 g, 3.04 mmol) in DMF (5 ml) is added-potassium carbonate (0.631 g, 4.56 mmol) followed by bromoethane (0.238 ml, 3.19 mmol) and the reaction mixture is stirred at room temperature for 5 days. The solvent is removed in vacuo and the crude is partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer is separated, washed with water (2×100 ml), saturated sodium hydrogen carbonate solution (100 ml) and concentrated in vacuo to afford the titled compound as a pale yellow solid which is used crude in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.[CH:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29](=[O:32])[NH:30]/[N:31]=[C:5]2/[C:6](=[O:20])[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8]3[C:4]/2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NNC(=O)NC1CCCCC1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NC2CCCCC2)c2cc(Br)ccc21)C(C)C
Yield: 89.9 %

Procedure:
By using 5-bromo-1-(2-diisopropylaminoethyl)isatin and 4-cyclohexylsemicarbazide, a method analogous to that described in Example 16 was carried out to obtain (E)-5-bromo-1-(2-diisopropylaminoethyl)isatin 3-(4-cyclohexylsemicarbazone) having a melting point of 155°-156° C. (yield: 89.9%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3]1.[C:12](O)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1])=[O:20]
Reactant: O=C(O)c1ccccc1O
Reactant: Cn1ccc2c(N)cccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cn1ccc2c(NC(=O)c3ccccc3O)cccc21
Yield: 60.7 %

Procedure:
A solution of 5 g of 1-methyl-1H-indol-4-amine [prepared according to Ley (J. Chem. Soc. Chem. Com. (1982) p. 1356], 4.7 g of salicylic acid and 7 g of dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran was refluxed for 24 hours and 20% of salicylic acid and of dicyclohexylcarbodiimide were added after 5 hours of refluxing. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica (eluant: methylene chloride) to obtain 5.5 g of 2-hydroxy-N-(1-methyl-1H-indol-4-yl)benzamide melting at 211° C.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:23]=[C:22]([C:24]([O:26]C)=O)[C:21]([N:28]4C5C=CC=CC=5[C:34]5[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:20][C:15]=3[C:16]([O:18]C)=O)[C:11]3[C:6](=CC=CC=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:41]1([Li])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:45]1[C:46]2[N:28]([C:21]3[CH:20]=[C:15]([C:16]([OH:18])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:14]([N:12]4[C:11]5[CH:34]=[CH:29][CH:30]=[CH:31][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[CH:23][C:22]=3[C:24]([C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=3)([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:15]=3)[OH:26])[C:29]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)c(C(=O)OC)cc1-n1c2ccccc2c2ccccc21
Reactant: [Li]c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)c1cc(-n2c3ccccc3c3ccccc32)c(C(O)(c2ccccc2)c2ccccc2)cc1-n1c2ccccc2c2ccccc21

Procedure:
The compound is synthesised by the same procedure as for the corresponding step of Example 5 by reaction of 73 g (140 mmol) of dimethyl 2,5-biscarbazol-9-ylterephthalate with 400 ml (600 mmol) of 1.6 M phenyllithium solution. The yield is 89 g (115 mmol), corresponding to 82% of theory.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[NH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:25]([C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)=[O:26])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)[nH]n1
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg, 0.100 mmol, from Step B of Example 1.1), 3-methyl-1H-pyrazole-5-carboxylic acid (18.9 mg, 0.150 mmol), and triethylamine (0.139 mL, 1.00 mmol) in DMF (0.5 mL) was added 1-propylphosphonic acid anhydride solution (50 wt. % in ethyl acetate, 122 μL, 0.200 mmol). The mixture was stirred for 2 h, quenched with water and purified by preparative HPLC/MS. The resultant lyophilate was dissolved in DCM, treated with MP-carbonate resin (˜100 mg). The mixture was stirred for 30 min and filtered to remove the resin. The solvent was removed under reduce pressure to afford the title compound (26.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.66 (bs, 4H), 3.82 (s, 2H), 3.88 (bs, 2H), 4.02 (bs, 2H), 6.38 (s, 1H), 7.14 (t, J=8.59 Hz, 2H), 7.99-8.09 (m, 2H). Exact mass calculated for Cl17H19FN4O2: 330.2. Found: LCMS m/z=331.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:23][CH2:24][CH2:25][CH2:26][P:27](=[O:30])([OH:29])[OH:28].[BH3-]C#N.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:11][C:12]([CH2:15][NH:23][CH2:24][CH2:25][CH2:26][P:27](=[O:28])([OH:30])[OH:29])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(C=O)nc2-c2ccncc2)cc1
Reactant: NCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccncc2)cc1

Procedure:
Following General Procedure M, 3-(4-ethyl-phenyl)-[2,4′]-bipyridinyl-6-carbaldehyde (Compound 58, 50 mg, 0.17 mmol), (3-amino-propyl)-phosphonic acid (24 mg, 0.17 mmol), Bu4NOH (0.17 ml, 0.17 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.17 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].N([O-])=[O:12].[Na+].FC(F)(F)C(O)=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:12])#[N:2]
Reactant: O=N[O-]
Reactant: N#Cc1cccc(CN)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1cccc(CO)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
m-Cyanobenzylamine (13.2 g), sodium nitrite (10.4 g), and dimethylformamide (100 ml) were mixed together, and the mixture was vigorously stirred at room temperature. Trifluoroacetic acid (22.8 g) was added dropwise to the mixture over one hour. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.9 g of m-cyanobenzyl alcohol (bp. 128-130° C./400 Pa) (yield 52%). The purity of the product was 98%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:12]([CH3:13])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc(Br)cc1
Product: Cc1nnc(-c2ccc(Br)cc2)o1

Procedure:
The title compound was prepared from 4-bromobenzoic hydrazide and triethyl orthoacetate following a similar procedure to that of Description 35, to afford fine white crystals (77%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:11]=[CH:12][CH3:13])[OH:10])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:13][CH:12]1[CH2:3][C:1]([CH3:2])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[O:10])[CH2:11]1
Reactant: C=C(C)C1CCCCC1(O)C=CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=CCCCCC(=O)CC(C)C1

Procedure:
A mixture of 2-isopropenyl-1-propenylcyclohexan-1-ol (0.090 g; 5.10-4 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.008 g; 0.2.10-4 mol) in tetrahydrofuran (5cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 6 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying with magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), alcohol starting material (0.050 g) is obtained together with 3,5-dimethylcyclodec-5-en-1-one (0.023 g), which has the following characteristics:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12](F)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH:18][CH:19]1[CH2:22][O:21][CH2:20]1.O>CN(C)C=O>[Cl:3][C:4]1[C:12]([O:18][CH:19]2[CH2:22][O:21][CH2:20]2)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OC1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of 0.76 g (19 mmol) of 60 percent in mineral oil sodium hydride in dry N,N-dimethylformamide was prepared in a flask under a nitrogen blanket and to it was added 2.02 g (8.0 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid in portions with stirring at ambient temperature. The mixture was allowed to cool and then 0.71 g (9.6 mmol) of 3-hydroxyoxetane was added dropwise with stirring. There was an exotherm. After one hour, the reaction appeared to be complete and water was added cautiously. The resulting aqueous solution was extracted with ether and was then acidified with 1N aqueous hydrochloric acid. The resulting mixture was extracted three times with ethyl acetate and the three extracts were combined, washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was crystallized with a mixture of acetone and hexane to obtain 1.41 g of the title compound as white crystals melting at 180-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][C:5]([CH2:6][C:7]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)(C(OCC)=O)[C:8]([O:10]CC)=[O:9])=[CH:4][C:3]=1[Cl:45].[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[C:40]([C:41]([F:43])([F:42])[F:44])=[CH:39][C:5]([CH2:6][CH:7]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[Cl:45]
Reactant: CCOC(=O)C(CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F

Procedure:
To a solution of 17.90 g (27.41 mmol) diethyl 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-ethyl}-malonate (Intermediate product 67) in 1200 mL EtOH was added 5.48 g (137.00 mmol) NaOH in 500 mL water and the mixture was refluxed for 4 hours. EtOH was evaporated off i. vac. and the aqueous phase was acidified to pH 2 with conc. aqueous HCl. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 2-(tert-butyldimethylsilyloxy)-1-(4-nitrophenyl)ethanone (0.54 g, 1.83 mmol) in methanol (60 mL) was added an aqueous solution (15 mL) of ammonium chloride (0.98 g, 18.3 mmol), followed by the addition of Zinc (1.2 g, 18.3 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to a small volume, then hen partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give 1-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone as a white foam (0.4 g, 82%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CCc2c(Br)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-1 (1.56 g, 7.3 mm) in DMF (5 mL) was added TBDMSCl (1.3 g, 8.7 mmol) and imidazole (1.24 g, 18.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution (30 mL) and extracted with EA (2×50 mL). The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford 2.1 g (88%) of (S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane IND INT-3 as white solid. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; no M+ observed, tR=5.73 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.07 (t, J=7.7 Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.00 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.73 (dt, J=16.5, 8.3 Hz, 1H), 2.42 (dddd, J=12.8, 8.0, 7.1, 3.0 Hz, 1H), 1.91 (dtd, J=12.8, 8.9, 7.1 Hz, 1H), 0.98-0.88 (m, 9H), 0.14 (d, J=7.4 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>>[ClH:16].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:22]
Reactant: CN(C)CCCl
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: CC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 104.2 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and dimethylaminoethyl chloride hydrochloride (4.32 g) were treated to obtain 3.5 g of 1-dimethylaminoethyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 200°-201° C).