Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.[CH:13]1([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([N:23]([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH:13]3[CH2:15][CH2:14]3)[CH2:22][CH2:21]2)[CH3:24])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)COc1cncc(Cl)c1
Reactant: CNC1CCN(CC2CC2)CC1
Product: CN(C(=O)COc1cncc(Cl)c1)C1CCN(CC2CC2)CC1
Product: Cl

Procedure:
The title compound was synthesized from 2-(5-chloropyridine-3-yloxy)acetic acid and 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine in the same manner as in Example 95.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Cl[CH:15]([C:20]([CH3:22])=O)[C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>O1CCCC1>[CH3:22][C:20]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 79 °C
Yield: 95.6 %

Procedure:
4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved in tetrahydrofuran (300 ml) at room temperature, and then methyl 2-chloroacetoacetate (12.2 ml, 0.1 mol) was added slowly for about 20 minutes therein while stirring. After completion of addition, the mixture was stirred again at room temperature for 30 minutes, and then the mixture was heated and refluxed at 78 to 80° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Subsequently, 50% aqueous solution of sodium hydroxide (150 ml) was added and stirred for 20 minutes. The resultant organic layer was separated by extraction with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to thereby yield 28.8 g of the title compound (yield: 95.6%).
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:11])[CH3:10])=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]([C:9](=[O:11])[CH2:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC=C(OC(C)=O)C(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 545 mg (3.5 mmol) of 1-methoxy-3-oxobut-1-en-2-yl acetate in THF (14.2 mL) −78° C. was added LHMDS (3.45 mL of a 1 M solution in toluene) dropwise. After stirring for 20 min at −78° C., the reaction mixture was treated with 0.4 mL (3.5 mmol) of benzoyl chloride dropwise, then removed from the cold bath and allowed to warm to room temperature and continue stirring for 18 h. The reaction was quenched with 10 mL 10% aq HCl and extracted with diethyl ether (3×10 mL). The organic fractions were combined, washed with sat. aq. NaCl, dried (Na2S0), and concentrated under reduced pressure to provide 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate which was used the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[N:8]2[CH2:20][CH2:19][C:18]#[N:21])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: O=C1Nc2cc(Cl)ccc2C12OCCCO2
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN1C(=O)C2(OCCCO2)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 65 h
Yield: 72.2 %

Procedure:
A mixture of 6′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (8.85 g, 36.9 mmol), and benzyltrimethylammonuim hydroxide (40% aqueous solution, 1.46 mL, 3.69 mmol, 0.1 mole % ) in anhydrous DMF was heated to 65° C. Acrylonitrile (4.86 mL, 73.9 mmol, 2 eq) was added drop-wise by syringe under a dry N2 atmosphere. After stirring 65 hr. the reaction was cooled to room temperature and poured into water (750 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of 100% CH2Cl2 followed by CH2Cl2/CH3OH/NH4OH (99.7/0.2/0.1) to give the title compound as a white solid (7.80 g, 73% yield). Anal: Calc'd for C14H13ClN2O3: C, 57.45; H, 4.48; N, 9.59. Found: C, 56.39; H, 4.35; N, 9.35. NMR (400 MHz, DMSO-d6): consistent. IR: consistent; MS: (EI+) m/z 292 [M+] 1 chlorine pattern observed. m.p.163-164° C.; HRMS: consistent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.CO[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[C@:32]3([C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]3=[O:41])[CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]2[C@:32]3([C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH2:20][C:16]4[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=4)[C:13]([NH:10][CH2:9][CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:22])[C:33]3=[O:41])[CH2:31]2)=[CH:28][CH:29]=1
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C(NCCCN1CCOCC1)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from form 3 3-morpholinopropan-1-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C31H32ClN3O3: 529, observed (M+H)+: 530.2 1H NMR (400 MHz, MeOD-d4) δppm 2.02-2.15 (m, 2 H) 2.24 (d, J=8.59 Hz, 2 H) 3.15 (br. s., 2 H) 3.23 (d, J=8.08 Hz, 2 H) 3.25-3.31 (m, 1 H) 3.47-3.57 (m, 4 H) 3.79 (t, J=12.38 Hz, 2 H) 4.06 (br. s., 2 H) 5.14 (s, 2 H) 6.09 (d, J=7.33 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.91 (d, J=8.08 Hz, 1 H) 7.09 (t, J=7.71 Hz, 1 H) 7.20-7.28 (m, 2 H) 7.28-7.37 (m, 2 H) 7.49 (t, J=7.71 Hz, 1 H) 7.53-7.61 (m, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 7.87 (s, 1 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH3:24]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH3:24])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: CBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 87.7 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0638 g, 0.217 mmol) and bromomethane (2.0 M in t-Butylmethyl ether, 0.250 mL, 0.500 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0739 g, 88.0%). EI-MS m/z 308 (M+) Rt (1.58 min).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:17])([F:16])[CH2:11][S:12](Cl)(=[O:14])=[O:13].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]([F:17])([F:16])[CH2:11][S:12]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:14])=[O:13]
Reactant: COC(C)(C)CCO
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (0.4 g, 3.4 mmol) and TEA (0.2 g, 2 mmol) in CH2Cl2 (6 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.12 g, 0.66 mmol). The solution was stirred at rt for 1 h. The organics were extracted with CH2Cl2 (25 mL) and washed with 0.1 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product as an oil (0.086 g, 50%). 1H NMR (400 MHz CDCl3) δ 4.41 (t, 2H, J=7.3 Hz), 3.87 (q, 2H, J=8.8 Hz), 3.14 (s, 3H), 1.94 (t, 2H, J=7.3), 1.16 (s, 6H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH2:37]([O:39][C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:41])[C:42]1[CH:49]=[CH:48][C:45](/[CH:46]=[C:15](/[C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:8]=2)\[CH3:16])=[CH:44][CH:43]=1)[CH3:38]
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid ethyl ester of melting point 90°-91° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[O:9][N:8]=[CH:7][CH:6]=1.O.[NH2:12][NH2:13]>C(O)CCC>[O:9]1[C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[CH:6][CH:7]=[N:8]1
Reactant: COC(=O)Cc1ccno1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)Cc1ccno1
Yield: 41 %

Procedure:
As described for example 112a, isoxazol-5-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 41%). 1H-NMR (300 MHz, DMSO): δ=3.65 (s, 2H), 4.31 (s, 2H), 6.32 (s, 1H), 8.46 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCC(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCC(F)(F)F)cc2c1=O
Temperature: 140 °C
Yield: 25.3 %

Procedure:
A mixture of 200 mg (0.628 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 1.08 ml (13.68 mmol) of 2,2,2-trifluoro-ethylamine in a closed vial is heated in a microwave reactor at 140° C. for 20 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase dried and concentrated to yield a precipitate which is filtered off and submitted to purification by medium pressure chromatography on a RP-C18 column (20 μM material) with tetrahydrofuran/water 4:3 as eluent, containing 0.1% TFA. During concentration of the fractions the product precipitates and is collected by filtration, giving 63 mg of a red powder, m.p. 250° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][N:20]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[CH:7]=3)[N:1]=2)[CH:22]=[CH:21][N:20]=1
Reactant: NC(=O)c1cc(CN2CCOCC2)ccc1N
Reactant: Cc1cc(C=O)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CN4CCOCC4)cc3c(=O)[nH]2)ccn1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-5-morpholin-4-ylmethyl-benzamide (0.58 g, 2.4 mmol) and 2-methyl-pyridine-4-carbaldehyde (0.3 g, 2.4 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 0.48 g, 2.7 mmol) and p-TSA (0.23 g, 1.2 mmol) and the reaction mixture was heated at 115° C. for 16 hours, and the solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanolic ammonia in dichloromethane) to give the title compound as a white solid. Yield: 0.18 g (22%). MP 267-268° C. 1H NMR (400 MHz, DMSO-d6): δ 11.74 (br s, 1H), 8.77 (d, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.94-7.83 (m, 3H), 3.75 (t, J=4.2 Hz, 4H), 3.74 (s, 2H), 2.77 (s, 6H), 2.53-2.46 (m, 4H). MS (ES+) m/z: 337.41 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:10]([C:13]1[C:14]([CH2:19][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccnc1C=O
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1C(C)C

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-isopropyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8])(=[O:4])=[O:3].[NH2:11][C:12]([CH3:16])([CH3:15])[C:13]#[N:14].C(N(CC)CC)C>O1CCCC1>[C:13]([C:12]([NH:11][S:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8])([CH3:16])[CH3:15])#[N:14]
Reactant: CC(C)(N)C#N
Reactant: CS(=O)(=O)CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C#N)NS(=O)(=O)CCS(C)(=O)=O
Temperature: 25 °C
Yield: 133.2 %

Procedure:
To a stirred solution of 5.00 g (24.2 mmoles) 2-(methylsulfonyl)ethylsulfonyl chloride (Example 32) in 50 ml dry tetrahydrofuran, a solution of 2.11 g (0.025 moles) 2-amino-2-methyl-propionitrile and 2.5 g (0.025 moles) triethylamine in 20 ml dry tetrahydrofuran were added dropwise over 13 minutes. During the course of the addition, the temperature of the mixture rose from 19° C. to 38° C. and a white precipitate formed. After the mixture cooled to room temperature, it was filtered. The solid, inorganic salts, was washed with tetrahydrofuran and ethyl ether. The filtrate and washings were stripped using a rotovap to give 8.2 g of a sticky white solid. Recrystallization of the solid from boiling ethanol gave 3.94 g of the above-identified product, melting point 151°-153° C.
Reaction SMILES: [F:1][C:2]1[C:12]2[NH:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.[Cl-].[Na+].O>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8](=[O:13])[CH2:9][CH2:10][NH:11][C:12]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)CCNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-fluoro-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one from Example 1B (220 mg, 1.2 mmol) in DMF (4 ml) was added sodium hydride (60%, 48 mg, 1.2 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and was stirred for 10 min. Tert-butyl bromoacetate (190 μl, 1.2 mmol) was added and the mixture was stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was reduced in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc:pet ether 60:40); yield 240 mg, 67%.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>COCCO>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: N#CC(CCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 18.6 parts of 2,2-diphenyl-4-bromobutyronitrile, 10.0 parts of 4-phenylpiperidine, 8.0 parts of N,N-diisopropylethylamine and 200 parts by volume of 2-methoxyethanol is heated at reflux for 16 hours. The solution is then cooled and stripped in vacuum. The resulting residue is partitioned between dilute sodium hydroxide and ether. Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil. This oil and the aqueous phase of the partitioning are combined, treated with aqueous sodium hydroxide and extracted with 1:1 ether-benzene mixture. The ether-benzene extract is dried over sodium sulfate and stripped in vacuum to give a solid. Crystallization of the solid from a mixture of skelly B and ether provided 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile, melting at 88° - 89.5° C. and having the following formula ##STR7##
Reaction SMILES: [OH:1][CH:2]([CH:7]([OH:34])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](=[N:31]\[O:32][CH3:33])/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=C[CH:36]=1.Cl[C:42](Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:33][O:32]/[N:31]=[C:24](/[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)\[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH:7]3[O:34][C:42](=[O:44])[O:1][CH:2]3[C:3]([O:5][CH2:6][CH3:36])=[O:4])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)C(O)C(=O)OC)cc2)cc1)c1ccccc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1OC(=O)OC1c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a stirring solution of methyl 2,3-dihydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (1.3 g, 2.8 mmol) in dichloromethane (20 mL) was added pyridine (1.4 g, 17.7 mmol) at −78° C. followed by solution of triphosgene (0.44 g, 15 mmol) in dichloromethane, and gradually warmed to RT then stirred at RT for 4 h. RM quenched with 1N HCl and extracted with dichloromethane. Organic layer was washed with water, NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to colourless oil which was purified by column (60-120 silica) using 20% ethyl acetate in pet ether to get the titled compound as colourless oil. (0.8 g, Yield: 58%) 1H NMR (300 MHz, CDCl3): δ 7.62-7.64 (m, 2H), 7.34-7.45 (m, 8H), 7.06-7.09 (d, 2H), 6.91-6.94 (d, 2H), 5.88-5.91 (d, 1H), 5.41-5.44 (d, 1H), 5.23 (s, 2H), 5.04 (s, 2H), 3.99 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: COc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methoxybenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13].[OH2:15].[C:16]1([CH3:26])C=CC(S(O)(=O)=O)=CC=1>C(OC(C)=C)(=O)C>[CH3:1][C:2]1[C:3](=[CH:10][CH:11]=[C:12]([O:13][C:16](=[O:15])[CH3:26])[CH3:14])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: O
Agent: C=C(C)OC(C)=O
Product: CC(=O)OC(C)=CC=C1C(C)=CCCC1(C)C
Yield: 14611.2 %

Procedure:
96 g of β-ionone are dissolved in 500 ml of isopropenyl acetate and treated with 0.6 g of p-toluenesulphonic acid monohydrate. The mixture is stirred at reflux temperature under an inert gas atmosphere for 24 hours. The excess isopropenyl acetate is distilled off from the mixture under a vacuum (temperature ≤50°) and then the mixture is treated several times with hexane in order to liberate residual amounts of isopropenyl acetate and concentrated again. In this manner, there are obtained 108 g of brown-red 4-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-2-acetoxy-but-2-ene (formula II; R = acetyl).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][CH:8]=2)[NH:3]1>C(OC(=O)C)(=O)C>[CH2:10]1[C:9]2=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]2[N:3]([C:14](=[O:16])[CH2:13][CH2:12]3)[C:2](=[O:1])[CH2:11]1
Reactant: O=C(O)CCc1cccc2c1NC(=O)CC2
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2cccc3c2N1C(=O)CC3
Temperature: 100 °C

Procedure:
1,2,3,4-Tetrahydro-2-oxo-8-quinolinepropanoic acid (2.1 g, 0.0096 mole) is dissolved in acetic anhydride (10 ml) and the solution is heated to 100° C. for one hour. Excess acetic anhydride is removed at reduced pressure and the residual anhydride is removed by addition of toluene and repeated concentration. The solid is recrystallized from ethyl acetate to yield pure 1,2,6,7-tetrahydro-3H,5H-benzo[ij]-quinolizine-3,5-dione, mp 136°-140° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)c1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile (from the previous step) (1 eq) in ethanol (0.1 M) was added Platinum Oxide (30 mol %). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 0.5 hour. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give 5-(4-acetylphenethyl)-3-chloropicolinonitrile as an off-white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[S:17])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)Nc1ccc(Cl)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and 4-chlorophenyl isocyanate. The analytical values are summarized in Table I.