Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([F:9])([F:8])C(OCC)=O.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:2]([F:9])[F:8])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
Ethyl chlorodifluoroacetate (25 mL, 0.20 mol) was added to 4-(benzyloxy)phenol (20.10 g, 0.10 mol), and potassium carbonate (41.90 g, 0.30 mol) in dimethylformamide (200 mL) and the mixture was stirred at 80° C. for 18 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 80° C. for 6 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 120° C. for 15 h. The mixture was cooled, poured into water (1000 mL) and extracted with ethyl acetate (500 mL). The organic fraction was washed with aqueous sodium hydroxide (1M, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (90:10) to give the title compound as a colorless solid (6.67 g, 27%). 1H NMR (360 MHz, CDCl3) δ 5.05 (2H, s), 6.42 (1H, t, J 74 Hz), 6.94 (2H, m) 7.06 (2H, m), and 7.31-7.44 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:31]([C:40]([F:43])([F:42])[F:41])[CH:30]=1>CN(C=O)C>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]3[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[CH:5]4)=[CH:30][C:31]=2[C:40]([F:41])([F:42])[F:43])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 73.2 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (107 mg, 0.391 mmol) and cesium carbonate (191 mg, 0.587 mmol) in DMF (2 mL) was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (123 mg, 0.47 mmol). The reaction was heated at 75° C. for 5 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (143 mg). LCMS m/z=500.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.52-1.67 (m, 3H), 1.68-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.24 (m, 5H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.95 (dd, J=15.6 and 5.4 Hz, 1H), 3.35-3.45 (m, 1H), 3.45-3.55 (m, 1H), 3.83-3.92 (m, 1H), 4.10-4.18 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 5.10 (s, 2H), 6.19 (s, 1H), 6.90 (dd, J=8.8 and 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.1 and 1.3 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31](O)=[O:32])=[N:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:31]([C:26]4[CH:27]=[CH:28][C:29](=[O:30])[N:24]([CH3:23])[N:25]=4)=[O:32])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nc(C(=O)O)ccc1=O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cccc(F)c4)nc23)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (30 mg, 0.10 mmol), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (34 mg, 0.22 mmol), and HATU (84 mg, 0.22 mmol) was added 0.8 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The resulting fine yellowish suspension from the reaction mixture was filtered, rinsed with first DMF and then ether, to provide the final product as a yellowish solid (14.4 mg, 33% yield). MS (apci) m/z=434.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:31](C=O)C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([NH2:31])=[O:5]
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (205 mg) was dissolved in THF (5 ml) and thionyl chloride (0.06 ml) and DMF (0.01 ml) were added. The mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated under reduced pressure and re-dissolved in THF (5 ml). 28% Aqueous ammonia (3 ml) cooled to 5° C. was gradually added. The reaction mixture was stirred at room temperature for 30 min. and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→ethyl acetate) for purification and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (130 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: COc1cccc(C=O)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
A mixture of 3-methoxybenzaldehyde (10.0 g, 73.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (21.0 g, 146.9 mmol), sodium triacetoxyborohydride (31.1 g, 146.9 mmol), and acetic acid (4.4 mL, 73.45 mmol) in 1,2-dichloroethane (100 mL), was stirred at ambient temperature. After 19 h, a 2 N aqueous sodium carbonate solution (220 mL) was added portionwise. After stirring for 15 min, the aqueous layer was separated and extracted with methylene chloride (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to provide 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (16.0 g, 82%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.27-7.20 (m, 1H), 6.93-6.88 (m, 2H), 6.79 (dd, J=2.4, 8.2 Hz, 1H), 3.94 (s, 4H), 3.82-3.78 (m, 3H), 3.50 (s, 2H), 2.56-2.47 (m, 4H), 1.74 (t, J=5.6 Hz, 4H); ESI MS (m/z) 264 [M+H].
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[C:12]1[CH2:13][CH2:14][C:9]([CH3:16])([CH3:8])[CH2:10][CH2:11]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C)(C)CC1
Temperature: 65 °C
Yield: 13.7 %

Procedure:
To a toluene (5 mL) solution containing 4,4-dimethyl-cyclohexanone (500 mg, 4.0 mmol) was added methyl (triphenylphosphoranylidene)acetate (2.0 g, 6.0 mmol) and the reaction was heated to 60-70° C. for 48 h. The reaction was monitored by TLC. The reaction was cooled to room temperature, diluted with dichloromethane, washed with water, concentrated under vacuum, and the crude product was purified on a silica gel column to afford (4,4-dimethyl-cyclohexylidene)-acetic acid methyl ester (100 mg, 14% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:42])=[O:41])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added benzenesulfonyl chloride (31.8 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The organic layer was dried on sodium sulfate and evaporated to dryness to obtain the title compound. Yield: 20 mg (29.7%); 1H NMR (CDCl3, 300 MHz): δ 9.59 (s, 1H), 8.198-8.227 (d, 2H, J=8.7 Hz), 7.958-7.989 (d, 1H, J=8.7 Hz), 7.70-7.723 (d, 2H, J=6.9 Hz), 7.57-7.69 (m, 4H), 7.40-7.436 (d, 2H, J=8.7 Hz), 6.97-6.981 (d, 1H, J=2.1 Hz), 1.79 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH-:12].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[NH-:24]
Reactant: Nc1cnc2cccnc2c1Cl
Reactant: Nc1cnc2ccccc2c1Cl
Product: [NH-]c1cnc2ccccc2c1Cl
Product: [NH-]c1cnc2cccnc2c1Cl

Procedure:
In step (1) of Reaction Scheme I, a 4-chloroquinolin-3-amine or 4-chloro[1,5]naphthyridin-3-amine of Formula XX is reacted with an acid halide of Formula Hal-Z—CH2—C(O)—Hal to provide an N-(4-chloroquinolin-3-yl)amide or N-(4-chloro[1,5]naphthyridin-3-yl)amide of Formula XXI. The reaction can be carried out by heating a solution of a compound of Formula XX and the acid halide in a suitable solvent such as 1,2-dichloroethane. Some acid chlorides of Formula Hal-Z—CH2—C(O)—Hal are commercially available; others can be prepared using conventional synthetic methods. Some 4-chloroquinolin-3-amines and 4-chloro[1,5]naphthyridin-3-amines of Formula XX are known. Others can be prepared using conventional synthetic methods; for example, by reduction of known 4-chloro-3-nitroquinolines and 4-chloro-3-nitro[1,5]naphthyridines.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][C:3]=1[O:11][CH3:12].C[O:14][C:15]1C=C([CH:21]=[CH:22][C:23]=1[N+]([O-])=O)C(N)=N>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:22]([CH2:23][CH2:15][OH:14])=[CH:21][N:8]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(N)=S)ccc1N
Reactant: COc1cc(C(=N)N)ccc1[N+](=O)[O-]
Product: COc1cc(-c2ncc(CCO)s2)ccc1N

Procedure:
2-[2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is prepared analogously to the processes described above. For the cyclisation, 4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82, 2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 32.7 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 77 mg of the target compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>C(#N)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Temperature: 22 °C
Yield: 98.7 %

Procedure:
A solution of L-proline-L-isoleucine benzylamide (10.22 g, 32.20 mmol), and sodium carbonate (6.824 g, 64.39 mmol, 2.0 eq), in acetonitrile (150 mL) was warmed to reflux until homogeneous, cooled to 22° C., and treated with benzyl 2-bromoacetate (14.75 g, 64.39 mmol, 2.0 eq). The flask was returned to the oil bath and warmed to reflux until TLC indicated the reaction was complete. The heterogeneous solution was filtered, concentrated to a residue, taken up in ethyl acetate (400 mL), and washed with satd aq NaHCO3 (2×50 mL). The solution was dried (MgSO4), concentrated to a residue, and purified by flash chromatography (20% ethyl acetate in hexane) to provide 14.80 g (99%) of L-isoleucine, N-[1-(2-benzyloxy-2-oxoethyl)-L-prolyl] benzylamide as a colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C-:5]#[N:6].[Na+].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O>O.CO>[CH3:2][N:3]([CH3:4])[CH:13]([C:9]1[S:8][CH:12]=[CH:11][CH:10]=1)[C:5]#[N:6]
Reactant: O=Cc1cccs1
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C(C#N)c1cccs1
Temperature: 30 °C

Procedure:
A solution of 131.5 g. of dimethylamine hydrochloride in 200 ml of water was stirred and 59 g of sodium cyanide added. A solution of 112 g of 2-thiophenecarboxaldehyde in 100 ml of methanol was added from a dropping funnel while the temperature was kept below 30° C. The mixture was then maintained at 30° C. for 4 hours; it was then poured into 3 1. of water.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].C(OC)(=O)[CH2:13][C:14]([CH3:16])=[O:15].[CH3:20][C:21]([OH:25])([CH3:24])[CH:22]=[CH2:23].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>>[CH2:1]([CH2:13][C:14](=[O:15])[CH3:16])/[CH:2]=[C:3](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])\[CH3:5].[CH3:10][C:9](=[CH:8][CH2:7][CH2:6][C:3](=[O:4])[CH3:2])[CH3:11].[CH3:20][C:21]([OH:25])([CH3:24])[CH:22]=[CH2:23]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: COC(=O)CC(C)=O
Agent: C=CC(C)(C)O
Agent: CC(C)[O-]
Agent: [Al+3]
Product: CC(=O)CC/C=C(\C)CCC=C(C)C
Product: CC(=O)CCC=C(C)C
Temperature: 165 °C

Procedure:
A mixture of 637 g of linalool (91% pure), 36 g of methyl acetoacetate, 6 g of 3-methyl-but-1-en-3-ol and 8.6 g of aluminum isopropylate was heated to 165° C. in the apparatus described in Example 12, and 642 g of methyl acetoacetate and 211 g of 3-methyl-but-1-en-3-ol were added dropwise in the course of 10 hours whilst maintaining a reaction temperature of 165° C., the temperature at the 2nd theoretical plate being kept at about 100° C. After a further 4 hours' reaction time at 165° C., the mixture was worked up by distillation. 681 g of geranylacetone, 212 g of 2-methyl-hept-2-en-6-one and 37 g of unconverted 3-methyl-but-1-en-3-ol were obtained. The selectivities achieved are accordingly as follows: 87% based on 3-methyl-but-1-en-3-ol, 94%, based on linalool, and 88%, based on methyl acetoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15].[CH3:31]CCCCC.[H-].[Na+].CI>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH:22]([CH3:31])[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: Cn1ccc(-c2ccc(C(=O)c3cccc4c3Nc3ncccc3CN4)c(Cl)c2)n1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Nc2cccc(C(=O)c3ccc(-c4ccn(C)n4)cc3Cl)c2Nc2ncccc21
Reaction time: 2 h
Yield: 47 %

Procedure:
Under anhydrous conditions, a solution of [2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-methanone of Example 19 (0.382 g, 0.92 mmol) in 10 mL of tetrahydrofuran was added dropwise to a stirred slurry of hexane washed sodium hydride (0.025 g, 1.02 mmol) in 2 mL of tetrahydrofuran. After the gas evolution ceased, methyl iodide (1 mL) was added and stirring was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed and the crude product purified by flash chromatography (on silica Merck-60, dichloromethane-ethyl acetate 2:1) to give the title compound (0.18 g, 47%). Crystallization from diethylether provided a light yellow solid (0.16 g), m.p. 249-250° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:19][CH2:20][NH2:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]2.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1c(C)c(C)c2c(c1CCN)CCC(C)(C)O2
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCOc1c(C)c(C)c2c(c1CCNS(=O)(=O)c1ccc(C)cc1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37.2 %

Procedure:
To a solution of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (450 mg, 1.8 mmol) in THF (4.2 mL) at 23° C. was added tosyl chloride (390 mg, 2.0 mmol) and pyridine (270 μL, 3.4 mmol). The reaction mixture was stirred at room temperature for 45 min, diluted in 50 mL EtOAc, washed with 1 M aqueous citric acid (2×25 mL) and brine (1×25 mL). The remained organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution 5→35% EtOAc/Heptane) to produce 300 mg N-(2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethyl)-4-methylbenzenesulfonamide. 1H NMR (CDCl3, 400 MHz) 7.48 (d, 2H), 7.09 (m, 8H), 5.20 (s, 1H), 4.82 (s, 2H), 3.55 (s, 3H), 3.10 (q, 2H), 2.70 (t, 2H), 2.45 (t, 2H) 2.35 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.65 (t, 2H), 1.20 (s, 6H) ppm.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:19][S:20]([CH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]2[C:37]([NH2:38])=[CH:36][N:35]=[C:34]3[CH:39]=[CH:40][S:41][C:33]=23)[CH2:27][CH2:26]1)(=[O:22])=[O:21]>O1CCCC1.C(O)C>[CH3:19][S:20]([CH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([N:31]2[C:32]3=[C:33]4[S:41][CH:40]=[CH:39][C:34]4=[N:35][CH:36]=[C:37]3[N:38]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:27][CH2:26]1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CCS(C)(=O)=O)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (52 mg, 0.59 mmol) and triethyloxonium tetrafluoroborate (0.11 g, 0.59 mmol) in tetrahydrofuran (1 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of N7-{trans-4-[2-(methylsulfonyl)ethyl]cyclohexyl}thieno[3,2-b]pyridine-6,7-diamine (83 mg, 0.23 mmol) in ethanol (2 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 1.1%). LCMS calculated for C19H26N3O3S2 (M±H)+: m/z=408.1. Found: 408.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[N:12]1([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:21]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nn1cnc2cnc3ccccc3c21
Temperature: 130 °C
Reaction time: 23 h

Procedure:
A suspension of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (6.50 g, 23.7 mmol) in 100 mL of toluene was treated with triethyl orthoformate (8.68 mL, 52.2 mmol) and pyridine hydrochloride (0.14 g, 1.2 mmol) and heated to 130° C. under an atmosphere of nitrogen. After 23 h, the reaction mixture was concentrated under reduced pressure to yield a red/brown oil. The oil was dissolved in CHCl3 (150 mL) and washed with water (2×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6.74 of tert-butyl N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamate as a red/orange oil.