Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:37][C:18]3[C:19](=[O:36])[N:20]([C:23]4[CH:24]=[N:25][C:26]([O:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl.O>[C:38]([N:33]1[CH2:34][CH2:35][CH:30]([O:29][C:26]2[N:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][C:17]4[CH:16]=[C:15]([C:12]5[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=5)[S:37][C:18]=4[C:19]3=[O:36])=[CH:28][CH:27]=2)[CH2:31][CH2:32]1)(=[O:40])[CH3:39]
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(OC2CCNCC2)nc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(Oc2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)CC1
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
Add pyridine (0.50 mL, 6.18 mmol) to a mixture of 2-(4-chloro-phenyl)-6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride (0.741 g, 1.56 mmol) in dichloromethane at room temperature. After stirring for 5 min, add acetyl chloride (0.16 mL, 2.33 mmol) to the mixture and stir overnight at room temperature. Dilute the mixture with water, extract into dichloromethane (3×50 mL), then dry over sodium sulfate, filter, and concentrate. Purify the residue using silica gel flash column chromatography (1-3% methanol/dichloromethane) and concentrate on high vacuum to yield the titled compound (0.678 g, 90%). MS/ES m/z (37Cl) 483 [M+].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[N:6]#[C:7][NH2:8].[ClH:9]>C(COC)OC>[ClH:9].[N:1]1([C:7]([NH2:8])=[NH:6])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: N#CN
Agent: Cl
Solvent: COCCOC
Product: N=C(N)n1cccn1

Procedure:
In a 500 ml four-necked flask fitted with gas inlet tube and gas outlet tube, internal thermometer and reflux condenser with in each case two safety wash bottles connected upstream and downstream, 34.1 g (0.5 mol.) of pyrazole and 21.0 g (0.5 mol.) of cyanamide are dissolved in 330 ml of dimethoxyethane. At 80° C., dry hydrogen chloride gas is introduced into the reaction solution at a rate of about 15 l/h for about 50 minutes. The solution is then allowed to cool and the precipitated solid is removed by filtration. The product obtained is dried under reduced pressure (100 mbar, 80° C.) to give 1H-pyrazole-1-carboxamidine hydrochloride in the form of a colorless, finely crystalline solid. Yield: 70.6 g (96%), melting point: 160 to 168° C. (literature: 165 to 166° C.) 13C-NMR (DMSO-d6) δ 152.3, 146.0, 131.5, 111.9.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH2:17].Cl.[OH-].[Na+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[NH:17][CH2:16][CH2:15]2
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)C(c1ccc(F)cc1)NCC2
Reaction time: 3 h

Procedure:
50 parts of p-fluorobenzaldehyde and 65 parts of 3,4-dimethoxyphenethylamine are combined and heated over a steam bath in a nitrogen atmosphere for 90 minutes. Then 800 parts by volume of 20% by weight hydrochloric acid is added and heating is continued for an additional 3 hours. The reaction mixture is cooled, made alkaline with sodium hydroxide and extracted with methylene chloride. The organic layer is dried over anhydrous calcium sulfate and stripped in vacuo to give 6,7-dimethoxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline. After crystallization from a mixture of ethyl ether and n-hexane, that product melts at about 145°-150°C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]([O:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29](=[O:30])[O:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([N:8]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=[CH:9]3)=[CH:38][CH:39]=2)(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc(-c4ccccc4)c3-c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,5-diphenylimidazole and 4-{2-[({[(4-Methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid: MS (ESI) m/z 538 [M+H]+, 536 [M−H]−, 1H-NMR (CDCl3) δ 2.43 (3H, s), 2.84 (2H, t, J=6.6 Hz), 4.22-4.28 (2H, m), 6.86-6.95 (2H, m), 7.03-7.08 (4H, m), 7.21-7.52 (10H, m), 7.73 (1H, s), 7.85-7.90 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:4]=1[C:22]([OH:24])=O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH2:36]([N:38]([CH2:41][CH:42]([OH:45])[CH2:43][NH2:44])[CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH2:36]([N:38]([CH2:41][CH:42]([OH:45])[CH2:43][NH:44][C:22]([C:4]1[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:6]2[C:11]([C:3]=1[O:2][CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:39][CH3:40])[CH3:37]
Reactant: COc1ccc(-n2c(C(=O)O)c(OC)c3ccccc32)c(OC)c1
Reactant: CCN(CC)CC(O)CN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccc(OC)cc1OC
Temperature: 0 °C

Procedure:
16.8 g of 3-methoxy-1-(2',4'-dimethoxyphenyl)-indole-2-carboxylic acid and 7 ml of triethylamine are dissolved in 50 ml of methylene chloride and the solution is added dropwise to 4 ml of thionyl chloride in 5 ml of methylene chloride. 8 g of 3-(N,N-diethylamino)-2-hydroxypropylamine dissolved in 10 ml of methylene chloride are added dropwise to this solution. The solution is poured into ice-water, the mixture is extracted with methylene chloride and the organic phase is washed with water, dried and evaporated. The 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxy-1-(2',4'-dimethoxyphenyl)-indole which remains is dissolved in isopropanol, and gaseous hydrogen chloride is added to the solution, whereupon the hydrochloride of the title compound crystallises out. Yield: 13.4 g, melting point: 166°-168° C.
Reaction SMILES: C[C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[BH4-].[Na+]>>[CH3:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:7][CH2:2][N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from D11 using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to addition of sodium borohydride and no column chromatography was required. δH (CDCl3, 400 MHz) 7.11 (2H, d), 6.57 (2H, d), 3.69 (1H, br.s), 3.40 (6H, m), 2.83 (3H, s), 2.36 (4H, m), 1.45 (9H, s) [6 values corrected for incorrectly referenced TMS at 0.58 ppm on spectrum]. MS (ES+): 206.2, no molecular ion (MH+) observed.
Reaction SMILES: Br[CH2:2][C:3]1[NH:4][C:5](=[O:18])[NH:6][C:7]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[ClH:19].Cl.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:19].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:7]2[NH:6][C:5](=[O:18])[NH:4][C:3]=2[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:17])=[CH:10][CH:11]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCN(c3ccccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6.2 g of 4-(bromomethyl)-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 5.0 g of 1-(2-methylphenyl)piperazine dihydrochloride and 5.4 g of potassium carbonate in 100 ml of ethanol is stirred at room temperature for 24 hours. Water is added to the reaction mixture and the precipitate which forms is separated by filtration. The solid is then suspended in 2-propanol, 1 equivalent of hydrochloric acid is added, and the resulting solid is separated and recrystallized from 2-propanol/water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2H-imidazol-2-one hydrochloride melting at about 223°-225° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6]C(=O)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].C(O)(=O)C>O>[NH2:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=1[SH:8]
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.7 %

Procedure:
6-Bromo-2-benzothiazolinone (4.65 g, 20.0 mmole) and sodium hydroxide (15.4 g, 0.385 mole) were mixed in 40 ml water. The mixture was stirred at room temperature for 30 minutes to form a slurry, was then heated at 100° C. and became a clear solution. The mixture continued to stir at 100° C. overnight after which it was cooled to room temperature. While cooling in an ice bath, the pH of the solution was adjusted to 6 with acetic acid (22 ml). The resulting solid was collected by filtration, washed three times (3×) with water and dried under vacuum to give 4.60 g of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.23 (s, 1H), 6.98 (d, J=7.80 Hz, 1H), 6.59 (d, J=8.82 Hz, 1H), 5.41 (br, 2H). MS: (M+H)+=203/205, (M+H)+=406.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH2:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7](OC(C)C)=[O:8])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:4][C@@H:5]([CH2:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[CH2:7][OH:8])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](CNCc1ccccc1)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](CNCc1ccccc1)[C@@H](CO)Cc1cc(C)cc(-n2c(C)ccc2C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of 19 (400 mg, 0.82 mmol) in THF (20 mL) at 0° C. was added LiAlH4 (48 mg, 1.2 mmol) in several portions. The reaction mixture was allowed to stir at 0° C. for an additional 10 min then quenched with H2O (25 μL). The solvent was removed by rotary evaporation, and the crude product was purified by flash column chromatography (EtOAc:hexanes, 2:1-4:1) to give 20 (280 mg, 0.66 mmol, 80%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.12 (s, 6H), 2.39 (s, 3H), 2.64-2.67 (dd, J=2.0, 12.0 Hz, 1H), 2.70-2.90 (m, 2H), 2.98-3.03 (dd, J=5.5, 12.5, Hz, 1H), 3.40-3.44 (dd, J=3.0, 11.5 Hz, 1H), 3.56-3.58 (dd, J=3.0, 6.0 Hz, 1H), 3.65-3.69 (dd, J=7.5, 11.5 Hz, 1H), 3.76-3.79 (d, J=13.0 Hz, 1H), 3.83-3.86 (d, J=13.0 Hz, 1H), 3.90-3.94 (dd, J=5.0, 12.5 Hz, 1H), 3.99-4.03 (dd, J=5.5, 12.5 Hz, 1H), 5.15-5.17 (dd, J=1.0, 10.5 Hz, 1H), 5.23-5.27 (dd, J=1.0, 18.5 Hz, 1H), 5.80-5.96 (m, 3H), 6.86 (s, 1H), 6.99 (s, 1H), 7.24-7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 37.7, 46.4, 49.5, 54.0, 60.8, 70.9, 79.4, 98, 9, 106.9, 117.2, 120.4, 123.7, 127.6, 128.6, 128.7, 128.9, 135.0, 139.2, 149.8, 151.8, 160.6; LCQ-MS (M+H+) calcd for C27H36N3O2 434. found 434; LC-TOF-MS (M+H+) calcd for C27H36N3O2 434.28075. found 434.28071.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O>>[CH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:23]=1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Product: CCOC(=O)/C=C/c1ccccc1Cc1ccc2ccccc2c1

Procedure:
The benzyl bromide (500 mg) of example 1, step 2 was treated with 2-naphthylboronic acid according to the same procedure previously described to yield 360 mg of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:14]([I:15])=[CH:13][N:12]=[CH:11][N:10]=1.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[I:15][C:14]1[C:9]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: Clc1ncncc1I
Reactant: c1c[nH]nn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Ic1cncnc1-n1nccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 1H-1,2,3-triazole (63.2 mg, 0.915 mmol) in THF (Volume: 2411 μl), was added portion wise at 0° C., NaH (39.9 mg, 0.998 mmol). The reaction mixture was stirred at that temperature for 30 min, then 4-chloro-5-iodopyrimidine (200 mg, 0.832 mmol) was added. The reaction mixture was allowed to warm to room temperature. To this solution was added saturated aqueous NH4Cl and the mixture was allowed to stir for 5 min at which time it was diluted with ethyl acetate and extracted 2×. The combined organics were washed with brine 1×. The organics were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (90 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33][CH3:34])=[O:32])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[Cl-].[Li+]>CN(C)C=O>[CH2:8]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=2)[CH:11]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[CH:10]1[C:31]([O:33][CH3:34])=[O:32])[CH2:3][CH2:4][CH3:5]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC)ccc1C1c2cc(OCCC)ccc2C(c2ccc3c(c2)OCO3)C1C(=O)OC
Yield: 77.4 %

Procedure:
Methyl(1RS,2SR,3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.118 g, 0.19 mmol), lithium chloride (0.058 g, 1.37 mmol), tetrakis(tri-phenylphosphine)palladium(0) (0.018 g, 0.016 mmol) and ethyl 3-[tri-(butyl-1-yl)stannyl]benzoate (0.253 g, 0.58 mmol) were mixed in dry dimethylformamide (5 ml) and refluxed for 24 h. The product was filtered through celite and the celite washed with ethyl acetate. The combined filtrate was evaporated in vacuo and was shown to be a mixture of two components by TLC. Purification by column chromatography on silica-gel gave a less polar fraction: methyl(1RS,2SR,3SR)-3-[2-(but-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.038 g) which was obtained as a colorless oil. The title compound was the more polar component (0.08 g) which while contaminated with tin residues (1H-NMR) was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[C:10]#[N:11].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][CH:3]1[CH:9]([CH3:12])[C:10]#[N:11]
Reactant: [H][H]
Reactant: C=C(C#N)C1CC(C)(C)CC1C
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C#N)C1CC(C)(C)CC1C

Procedure:
A solution containing 1 equivalent of 2-(2,4,4-trimethyl-cyclopentyl)acrylonitrile 5 in toluene and 5% by weight of 5% palladium-on-charcoal is placed in an autoclave, under 20 bar of hydrogen, at 40° C. At the end of the reaction, the autoclave is purged with nitrogen and the solution is filtered through celite. The filtrate is concentrated. The crude product, obtained in the form of four diastereomers in proportions of 8:18:22:52, is purified by distillation.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31](F)=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncccn4)CC3)CC2)n1
Temperature: 110 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (10 mg, 0.036 mmol) and cesium carbonate (35 mg, 0.11 mmol) were stirred in NMP (2 ml) and 2-chloro-5-fluoropyrimidine (8.2 mg, 0.72 mmol) was added. The mixture was heated at 110° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:18]=[C:17]([CH2:19][Br:20])[CH:16]=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C(=O)c1ccccc1
Yield: 63.4 %

Procedure:
A mixture comprising 1.3 g of the 2-acetoxy-4-methylbenzophenone prepared in the step (c), 910 mg of N-bromosuccinimide and 20 ml of carbon tetrachloride was heated under reflux together with a small amount of benzoyl peroxide for one hour. The reaction mixture was cooled and filtered through a silica gel bed, and the silica gel was washed with 20% ethyl acetate/hexane. The filtrate and washings were concentrated together. The residue was subjected to silica gel column chromatography (7 to 10% ethyl acetate/hexane) to give 1.08 g of the title compound.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][OH:31]>>[CH3:30][O:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CO
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Product: COc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 4 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using methanol instead of 3-fluorobenzyl alcohol, the title compound (yield 4%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[C:16]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:17]=4[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[C:16]4[CH2:22][CH2:21][NH:20][CH2:19][C:17]=4[N:18]=3)=[CH:11][CH:12]=2)=[O:37])[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (3.27 g, 6.43 mmol) in DCM (40 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and the resulting residue was dissolved in the minimum MeOH and precipitated from Et2O to give a pale yellow solid (498 mg, 0.95 mmol, 15% yield).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C1COCC1.C(OCC)(=O)C>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 0.5 g of potassium t-butoxide and 0.1 g of 18-crown-6 in 3 mL of THF, a mixed solution of 0.7 g of ethyl 1H-indole-2-carboxylate and 3 mL of THF was added, and the resulting mixture was stirred at room temperature for 30 minutes. The solution was cooled with ice, 1.13 g of 4-bromobenzenesulfonyl chloride was added, and the resulting mixture was stirred at room temperature for 5 hours. To the solution was added 60 mL of ethyl acetate, the resulting mixture was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to obtain 1.44 g of ethyl 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carboxylate as a pale yellow syrup. FAB+: 408, 410
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:16])(=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C1C=CC=CC=1.CCCCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:7](=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[S:26])=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCCCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2 g. sodium in 250 ml. dry acetone, 15.7 g. octanamidine hydrochloride, and 15 g. 4-chlorophenyl isothiocyanate in 70 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(octanimidoyl)-2-thiourea, m.p. 98°-99° C. (from benzene-n-pentane); hydrochloride (18.7 g.), m.p. 155°-157° C. (from acetonitrile).