Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:59]=[CH:58][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:58][CH:59]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1

Procedure:
Prepared from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50.8 mg, 0.217 mmol, prepared according to the procedure for Example 19, Step C) and ±(3S*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (63 mg, 0.109 mmol) according to the procedure described for Example 143, Step B. Yield: 17 mg (20%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
A solution of N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (22.4 g, 77.3 mmol) is dissolved in 130 mL of THF and added dropwise under nitrogen to 10.6 g (77.3 mmol) of tyramine in 100 mL of THF at 0° C. Reaction reaches completion overnight according to TLC. The solvent is removed in vacuo. Purification on a silica gel column, eluted successively with 5% EtOAc/Hexane, 15% EtOAc/Hexane, and 35% EtOAc/Hexane, provides the title compound as a white solid, m.p. 132°-133° C. (dec.) (21.0 g, 72%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=4[CH:29]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:52]1[CH2:71][O:70][C:54]2([CH2:59][CH2:58][CH:57]([N:60]([CH2:62][C:63]3[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=3)[CH3:61])[CH2:56][CH2:55]2)[O:53]1>CN(C=O)C.C(N(CC)CC)C>[CH2:71]1[CH2:52][O:53][C:54]2([CH2:55][CH2:56][CH:57]([N:60]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([NH:67][C:26]([C:20]4[CH2:21][CH2:22][S:23](=[O:24])(=[O:25])[C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][O:2][CH2:3][CH2:4]7)=[CH:9][CH:10]=6)=[CH:29][C:18]=5[CH:19]=4)=[O:28])=[CH:68][CH:69]=3)[CH3:61])[CH2:58][CH2:59]2)[O:70]1
Reactant: CN(Cc1ccc(N)cc1)C1CCC2(CC1)OCCO2
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (200 mg) and 1-hydroxybenzotriazole (0.12 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]aniline (0.19 g) and triethylamine (0.2 ml) in DMF (3 ml), and the mixture was stirred for 64 hours. The mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:1) to give yellow crystals of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 15) (119 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:16]=[N:15]2)[N:3]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)cn2)n1
Yield: 38260.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example 140(A)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 mmol, 38%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH3:3])[CH:13]=1
Reactant: Cn1ccc2ccncc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(Br)c2ccncc2c1=O
Temperature: 15 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to 2-methyl-2,7-naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60 mL) at 10-15° C. After stirring at 15° C. for 1 h, the mixture was concentrated under vacuum. Purification by silica gel chromatography (DCM: MeOH=50:1 to 10:1) gave the title compound (0.45 g, 27.4%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 9.61 (1H, s), 8.86-8.85 (1H, d, J=5.6 Hz), 7.62-7.60 (1H, d, J=5.6 Hz), 7.56 (1H, s), 3.63 (3H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br)[CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1)[CH3:24]
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Yield: 16.9 %

Procedure:
A mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.05 g, 8 mmol), ethyl-4-bromobutyrate (1.56 g), and triethylamine (0.81 g, 8 mmol) in acetonitrile (35 ml) was heated at 55°-60° for 4 hr. The mixture was filtered, the filtrate concentrated and chromatographed (silica gel, ether) to give ethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate (0.59 g, 17%) as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]#[N:10])C.[H][H]>C(O)C.[Co]>[CH3:11][N:6]1[CH2:7][CH2:8][CH2:9][NH:10][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CN(C)CCC#N
Reactant: [H][H]
Agent: [Co]
Solvent: CCO
Product: CN1CCCNC(=O)C1
Yield: 75.1 %

Procedure:
A solution of 750 g of N-methyl-N-(2-cyanoethyl)glycine ethyl ester (prepared from methylaminopropionitrile and ethyl chloroacetate) in 1 liter of ethanol is hydrogenated in the presence of 60 g of Raney cobalt in an autoclave at a temperature of from 80° to 90°C and under a pressure of 100 to 120 atms. of hydrogen. The calculated quantity of hydrogen has been absorbed after about 1 hour. The hydrogenated solution is filtered off from the catalyst. The solid residue left after the ethanol has been evaporated is freed from any greases adhering to it by means of a little ethyl acetate, and the white product, which does not show any tendency towards discoloration in air, is fractionated in a high vacuum with 5 g of sodium methoxide. 424 g of 1-N-methyl-hexahydro-1,4-diazepin-3-one melting at 91°C are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)cccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-6-nitrobenzoic acid (11.9 g, 65.3 mmol), methyl p-toluenesulfonate (15.1 g, 81.1 mmol) and triethylamine (6.60 g, 65.3 mmol) in DMF (170 ml) was stirred under N2 at 60° for 18 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was dissolved in ETOAc and washed with a saturated solution of NaHCO3 followed by a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography over silica gel and elution with 50% toluene-50% CHCl3 gave methyl 2-amino-6-nitrobenzoate (7.6 g, 59.4%), m.p. 105°-107°.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34].C([O:43]C1C=CC=CC=1C(C=O)=O)C1C=CC=CC=1>CS(C)=O>[CH3:20][CH:21]([N:35]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:43])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34]
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(CC(C)N)c(OC)c1OC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)c(OC)c1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10.3 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in 5 ml of dimethylsulfoxide. 7.6 g of α-methyl-2,3,4-trimethoxyphenethylamine are dissolved in 6 ml of dimethylsulfoxide, and the solution is added to the 2-benzyloxyphenylglyoxal solution under ice-cooling. The mixture is stirred at 20° C. for 2 hours, whereby a solution of α-(α-methyl-2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.Br[CH:16]([CH3:20])[C:17](=O)[CH3:18]>C(#N)CC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][C:16]([CH3:20])=[C:17]([CH3:18])[N:12]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: CCC#N
Product: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C
Yield: 10 %

Procedure:
A suspension of 4-(3-chloropropoxy)benzamide ax54 (1.2 g, 5.62 mmol) and 3-bromobutan-2-one (1.02 g, 6.74 mmol) is heated in propionitrile (50 ml) at reflux for 10 days. The mixture is then concentrated and the resulting black mixture is filtered through a pad of silicagel, eluting first with dichloromethane (100 ml) and then with a 96:4 mixture of dichloromethane and dimethoxymethane to afford two fractions. The second fraction is concentrated, and the resulting yellow solid (0.67 g) is further purified by chromatography over silicagel (eluent: dichloromethane) to afford 330 mg of 2-[4-(3-chloropropoxy)phenyl]-4,5-dimethyl-oxazole i30 as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][S:7][C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3F)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CS(C)=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]2[S:7][C:8]3([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)=[CH:4][CH:3]=1
Reactant: CN1CCC(SCc2ccc(Cl)cc2)(c2ccccc2F)CC1
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC2(CC1)SC(c1ccc(Cl)cc1)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium methylsulfinylmethide is produced from 0.7 g of (50%) sodium hydride and 15 ml of dimethylsulfoxide as in Example 1c. A solution of 4.2 g of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free base of a, in 15 ml of dimethylsulfoxide is added to this solution over a three minute span. After total addition, the mixture is stirred at ambient temperature for one hour and then poured onto 70 ml of ice-water. The mixture is diluted with water to 120 ml total volume before being filtered to collect the crude product. The product is washed with water and then dissolved with ether. The ethereal solution is sequentially washed thrice with water and once with a saturated sodium chloride solution and dried to give yellow-white crystals. The crystals are chromatographed with ether through an alumina column to give white crystals, mp 121°-123° C. of 3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:38])/[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]=2[CH:37]=1.C([O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=O)(=O)C>N1C=CC=CC=1>[F:36][C:33]([F:35])([F:34])[O:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:10]2[C:9]3[CH:37]=[C:5]([CH2:4][C:3]4[N:38]=[C:44]([C:43]([OH:42])([CH3:48])[CH3:47])[O:1][N:2]=4)[CH:6]=[CH:7][C:8]=3[NH:14][C:13]3[N:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:12]=3[CH2:11]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: N/C(Cc1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2)=N\O
Solvent: c1ccncc1
Product: CC(C)(O)c1nc(Cc2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)no1
Temperature: 82 °C
Reaction time: 2 h

Procedure:
To a solution of (1Z)-N′-hydroxy-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]ethanimidamide (92 mg, 0.163 mmol, the product of Step A) in pyridine was added 2-acetoxyisobutyryl chloride (0.268 g, 1.63 mmol). The resulting mixture was heated at 80-84° C. for 1.5 hr, until LC-MS indicated the reaction was complete, and then the solution was concentrated to remove pyridine. The bright orange residue was dissolved in 5 mL of MeOH and K2CO3 was added. The mixture was stirred for 2 hr at 50° C., then another 0.5 g of K2CO3 was added and the solution was stirred for another 2 hr. The solution was filtered to remove solids and the filtrate was concentrated to remove MeOH. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (3:1-2:1) to give the title compound; Mass Spectrum: m/e=630 (M+1).
Reaction SMILES: F[C:2]1C(OC)=C(C(O[Si](C)(C)C)C#N)C=C(C)C=1.[ClH:19].Cl.[F:21][C:22]1[C:23](OC)=[C:24]([CH:29]([OH:35])[C:30](=[NH:34])[O:31][CH2:32][CH3:33])[CH:25]=[C:26](C)[CH:27]=1>>[ClH:19].[F:21][C:22]1[C:23]([CH3:2])=[C:24]([CH:29]([OH:35])[C:30](=[NH:34])[O:31][CH2:32][CH3:33])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1c(F)cc(C)cc1C(C#N)O[Si](C)(C)C
Reactant: CCOC(=N)C(O)c1cc(C)cc(F)c1OC
Agent: Cl
Product: CCOC(=N)C(O)c1cccc(F)c1C

Procedure:
By the procedure of Example 65, 2-(3-fluoro-2-methoxy-5-methylphenyl)-2-trimethylsiloxyethanenitrile (0.48 g., 1.79 mmoles) in 20 ml. of saturated ethanolic hydrogen chloride was converted to ethyl 1-(3-fluoro-2-methoxy-5-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride [0.36 g.; m.p. 105°-106° C. (dec)].
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>C(O)C>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccccc1
Yield: 106.6 %

Procedure:
A solution of 10 g (0.054, mole) of N-phenyl-1,2phenylenediamine and 9.94 ml (0.054 mole) of triethylorthoacetate in 200 ml of ethanol was heated to reflux for 4 hours. The solvent was removed and the residue partitioned between chloroform and water. The organic layer was separated, dried and removed to give 11.99 g of product as an oil.
Reaction SMILES: O.[Cl-].[NH4+].[Br:4][C:5]1[CH:6]=[C:7]([C:11]23[O:17][CH:16]2[CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([C@@:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Br:4])[CH:6]=2)[CH2:12][CH2:13][O:14][CH2:15][C@@H:16]1[OH:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1cccc(C23CCOCC2O3)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Yield: 108.1 %

Procedure:
Water (88 mL) and ammonium chloride (11.7 g) were added to a solution of (±)-6-(3-bromophenyl)-3,7-dioxa-bicyclo[4.1.0]heptane (17.5 g) in methanol (700 mL), followed by stirring at room temperature. Then, sodium azide (32.1 g) was added, followed by stirring at 80° C. for eight hours. After returning to room temperature, the excess of methanol was evaporated under reduced pressure. The residual aqueous layer was extracted with chloroform three times, and the organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C@:16]12[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:19][N:18](CC1C=CC=CC=1)[CH2:17]2)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C@:16]12[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:19][N:18]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:17]2)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@]12CCC[C@H]1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: COC(=O)[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 40 °C
Reaction time: 23 h
Yield: 44.9 %

Procedure:
Benzyl chloroformate (3.53 mL, 24.6 mmol) was added to a solution of (1R*,5R*)-3-benzyl-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid methyl ester (4.27 g, 16.46 mmol) in dichloromethane (50 mL) at room temperature, and the mixture was stirred on an oil bath at 40° C. for 23 hours. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→80:20→67:33) to give 2.24 g (45%) of the title compound as a colorless transparent oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C[O:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[C:15](=[O:26])[N:14]([CH3:27])[C:8]2[N:9]([CH3:13])[C:10]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:30](=[O:29])[CH2:31][N:32]([CH3:34])[CH3:33])=[CH:12][CH:11]=3
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: COC(=O)CN(C)C
Product: CN(C)CC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 80 above, with the compound from preparation 1.10E, 6-acetyl-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and dimethylglycine methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (346 mg, 74%).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:12](=[O:25])[C:11]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CI>O>[CH3:3][O:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:17])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:24])[C:12](=[O:25])[C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)C=O
Reactant: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Temperature: 25 °C
Yield: 67 %

Procedure:
Sodium hydride (60% in oil, 0.11 g) was suspended in diformaldahyde (2 ml), cooled with ice; then a dimethylformamide solution (6 ml) of 6-hydroxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 53, 0.8 g) was added slowly thereto. After stirring the mixture, methyl iodide (0.71 g) was added, and the mixture was stirred again at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography to afford the captioned compound (0.56 g, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=4[Cl:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,5-dichlorobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (56% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.38-7.30, 6.97, 4.12-3.23, 1.50, 0.80-0.67, 0.51-0.38, 0.16-0.06. MS (ES+) m/z 448.2 (M+1).