Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 78; 150 mg, 0.36 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (116 mg, 0.39 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.71 ml, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.75 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated under reduced pressure and the residue was purified using the MDAP to yield the title compound. 41 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[N+:18]([O-])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:18])=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline (1 g, 3.49 mmol) in AcOH (10.5 mL) was added iron powder (585 mg, 10.48 mmol) and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled to rt and water was added. The organic layer was extracted with EtOAc and was basified by using satd. sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo to provide N1-(3,5-difluorophenyl)-3,5-difluoro-benzene-1,2-diamine. The crude product was carried without further purification.
Reaction SMILES: [BH4-].[K+].[Cl:3][C:4]1C=[C:6]2[C:11](=O)[N:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=4)[N:14]=3)C(=O)[C:7]2=[CH:24][CH:25]=1.[OH2:26].[O:27]1[CH2:32][CH2:31]OCC1>CO>[Cl:3][C:4]1[CH:25]=[CH:24][CH:7]=[C:6]2[C:31]=1[CH:32]([OH:27])[N:10]([C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=3)[N:14]=1)[C:11]2=[O:26]
Reactant: C1COCCO1
Reactant: O
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: O=C1c2cccc(Cl)c2C(O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Potassium borohydride (3 g.) is added to 4-chloro-N-(7-chloro-1,8-naphthyridin-2-yl)-phthalimide (25.2 g.) in dioxane (500 cc.) and methanol (500 cc.). The mixture is stirred for 4 hours at a temperature of about 20° C and water (500 cc.) is then added. The precipitate is filtered off and washed with water (100 cc.) and then with a mixture (200 cc.) of equal parts of methanol and dioxane. This gives a crude product (20 g.) which is chromatographed on silica (0.05 - 0.2 mm) (6 kg.) as indicated below, the eluate being collected in fractions of 5,000 cc. Elution is carried out first with methylene chloride (10,000 cc.) and then with a mixture of methylene chloride and ethyl acetate (5/5 by volume) (40,000 cc.). This eluate, after concentration, yields (4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6 g.) melting at 270° C. Thereafter elution is carried out with the same mixture of methylene chloride and ethyl acetate (10,000 cc.). This eluate, after concentration, gives a mixture (1.6 g.) of the isomers 4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone and 7-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone. Finally, elution is carried out again with the same mixture of methylene chloride and ethyl acetate (20,000 cc.). This eluate, after concentration, yields 7-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.1 g.) melting at a temperature above 280° C.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][C:7]1([CH3:41])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:38](=[O:40])[CH3:39])[C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=3[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)C.O.[OH-].[Li+]>O1CCCC1.O>[C:38]([C:14]1[C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=2[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]2[O:8][C:7]([CH3:41])([CH2:6][CH2:5][C:4]([OH:42])=[O:3])[CH2:12][CH2:11][C:10]=2[CH:13]=1)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCCCOc2c(C(C)=O)cc3c(c2CCC)OC(C)(CCC(=O)OCC)CC3)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2c(C(C)=O)cc3c(c2CCC)OC(C)(CCC(=O)O)CC3)ccc(C(C)=O)c1O

Procedure:
A 191 mg sample of the product from Example 26 was saponified with lithium hydroxide monohydrate, (273 mg) in 5 ml of 3:2 tetrahydrofuran-water, using the procedure described in Example 4. After column chromatography on silica gel, racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid was obtained as a yellow, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)[C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[NH2:25][C@H:23]([CH3:24])[C:22]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:33]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)N)c1

Procedure:
Tert-butyl (R)-1-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylamino)-1-oxopropan-2-ylcarbamate (303a, 25 mg, 0.04 mmol) in DCM/TFA 1:1 (1 ml) was shaken for 1 h and then evaporated. Yield 25 mg (100%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:26][CH2:27][N:28]([C:2]2[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]3[O:9][CH:8]([CH3:10])[CH2:7][C:6]=3[C:11]=2[CH3:12])[CH2:29][CH2:30]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)O2
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)c(OC)c1
Yield: 53.7 %

Procedure:
By using 5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (480 mg, 1.88 mmol) synthesized in Reference example 53 and 1-(2,4-dimethoxyphenyl)piperazine (627 mg, 2.82 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 400 mg (yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24].[C:28](Cl)(=[O:31])[CH2:29][CH3:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:31])[CH2:29][CH3:30])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (4.7 mmoles) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-hydroxyphenylimino)-3-methyl-4-thiazoline is suspended in 40 ml of dry chloroform. 0.4 g (4.7 mmoles) of propionyl chloride (dissolved in 10 ml of chloroform) and 1.4 g (18 mmoles) of pyridine are added in that order. A slightly exothermic reaction produces, temporarily, a solution from which a yellow solid precipitates. After stirring for 3 hours at room temperature, a further 0.4 ml of propionyl chloride is added. The resulting yellow solution is allowed to stand for 3 days at room temperature and then evaporated to dryness in vacuo, the residue is distributed between water and ethyl acetate, the organic phase is dried and evaporated and the residue is recrystallized from isopropanol. Colorless crystals of m.p. 155°-159° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[CH:17]12[O:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2.C(N(CC)CC)C>>[CH:21]12[O:24][CH:17]([CH2:23][CH2:22]1)[CH2:18][N:19]([C:2]1[N:3]=[C:4]3[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[CH:7]=1)[CH2:20]2
Reactant: C1CC2CNCC1O2
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Solvent: CCN(CC)CC
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Yield: 92.2 %

Procedure:
500 mg (1.97 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 884 mg (5.91 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane and 820 μl (5.91 mmol) of triethylamine are placed in a microwave tube. The mixture is irradiated for 10 minutes at 150° C. The reaction medium is purified directly by passing through an RP18 reverse-phase column (eluent: H2O: 100% to CH3CN: 100%) to give 600 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:19][CH2:18][CH2:17][CH:11]([C:12]([O:14]CC)=[O:13])[CH2:10]2)=[CH:6][CH:5]=1>O.C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:19][CH2:18][CH2:17][CH:11]([C:12]([OH:14])=[O:13])[CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
A solution of LiOH (1.66 g) in H2O (25 mL) was added to the solution of ethyl 1-(4-chlorobenzyl)nipecotate in THF (60 mL) and CH3OH (20 mL). The reaction mixture was stirred at room temperature for 15 h. The solvent was removed under reduced pressure to afford an amorphous solid which was purified by column chromatography (SiO2, 50% CH3OH—CH2Cl2) to yield-1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as a pale yellow amorphous solid. The purity was determined by RPLC/MS (>95%); ESI/MS m/e 254.0 (M++H, C13H17ClNO2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccc(Cl)cc2C(F)(F)F)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.5 g, 4.99 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (0.835 mL, 5.99 mmol). The solution was then cooled to 0° C. before 4-chloro-2-(trifluoromethyl)benzoyl chloride (1.335 g, 5.49 mmol, commercially available from e.g. 3B Scientific or APAC) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (20 mL) and the solution was washed with water (10 mL), a saturated solution of sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off to yield the desired product in 1.445 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: O=S1(=O)CCNCC1
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCS(=O)(=O)CC3)ncc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.293 mmol) and thiomorpholine-1,1-dioxide (198 mg, 1.467 mmol) in 2-propanol (1 mL) was irradiated in the microwave for 90 minutes at 170° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(5-nitro-2-(1,1-dioxido-4-thiomorpholinyl)pyridin-4-ylamino)cyclohexanecarboxamide as a yellow powder (112 mg, 87% yield). MS, m/z (C19H29N5O5S): Calcd, 439.2. found, 440.1 [M+H].
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.O>[CH3:33][S:34]([O:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:13]2[N:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][CH:6]=3)=[CH:15][N:14]=2)[CH:18]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36 (6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) and methanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred at rt for 1.5 h. The reaction is diluted with H2O (10 mL) and washed with Na2CO3 solution (3×20 mL). The organic layer is washed with brine, dried over MgSO4 and concentrated to afford 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl methanesulfonate 37. MS (m/z) (M+1)+422.1.
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][OH:21])=[CH:6]\[C:7]([O:9]CC)=O.C[Si]([N:27]=[C:28]=[S:29])(C)C.O>O1CCCC1>[OH:21][CH2:20][CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[N:4]([CH2:3][C:2]([NH2:1])=[O:22])[C:28](=[S:29])[NH:27][C:7](=[O:9])[CH:6]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1ccccc1OCCO
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)Cn1c(-c2ccccc2OCCO)cc(=O)[nH]c1=S
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
To a solution of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(2-(2-hydroxyethoxy)phenyl)acrylate (1.0 g, 3.25 mmol) in tetrahydrofuran (15 mL) was added trimethylsilyl isothiocyanate (1.7 g, 12.9 mmol), and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into a flask containing water and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid, which was purified by flash chromatography (2-5% MeOH:CH2Cl2) to give the title compound (330 mg, 31.7%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[C:21]1([C:13]2([C:16]([OH:18])=[O:17])[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
9.3 g Ethyl 1-(3-phenylpropyl)-4-phenyl-4-piperidine-carboxylate (Formula I: R1 =hydrogen, R2 =COOEt, X=Y=CH2), prepared according to the procedure described in U.S. Pat. No. 2,914,532, incorporated herein by reference, was taken up in 35 ml water and 12 ml ethanol with 2.3 g sodium hydroxide, then refluxed for 24 hours and stirred at room temperature for the next two days. The product mixture was poured into water, the solution was acidified with acetic acid, and a precipitate appeared. The precipitate was washed well with water. The product was recrystallized from 4 liters of water and was washed with water, ethanol and ether, yielding 4-phenyl-1-(3-phenylpropyl)-4-piperidinecarboxylic acid, as a white powder, which was used without further purification in the next preparation.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[CH3:33][O:34][CH2:35][CH2:36][N:37]([CH3:38])[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:31])([F:1])[F:32])=[N:4][N:5]=4)[N:8]=3)[CH2:13][CH2:14]2)=[CH:30][CH:29]=1
Reactant: CNCCOC
Reactant: O=C(O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: COCCN(C)C(=O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 50 %

Procedure:
Obtained in 50% yield by an analogous method to Example 19, starting from 4-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]butanoic acid and N-(2-methoxyethyl)methylamine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C(NC(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.C(OCC)(=O)C>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][NH:13][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CC(C)(O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cn1cc([N+](=O)[O-])c(C(=O)NCC(C)(C)O)n1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a suspension of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (0.9 g, 5.26 mmol) and 1-amino-2-methylpropan-2-ol (469 mg, 5.26 mmol) in THF (20 mL) cooled to 0-5° C. were added N,N-diisopropylamine (3.67 mL, 21.0 mmol) and 1-propanephosphonic acid cyclic anhydride (8.37 mL, 13.1 mmol, 50% solution in ethyl acetate). The mixture was stirred at 70° C. for 16 hours, cooled to ambient temperature, poured into ethyl acetate (50 mL) and extracted with HCl (1 M, 20 mL). The organic phase was washed with water and brine. The aqueous layers were back-extracted separately with ethyl acetate and dichloromethane. The combined organic layers were dried and concentrated in vacuo to give 1.4 g crude product. The crude material was purified by silica gel chromatography using a methanol/ethyl acetate gradient to give the title compound as colorless foam (391 mg, 31% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, 8-chloro-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-chloro-1-(2-hydroxyethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:14][C:15]([F:26])([F:25])[C:16](Cl)=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(Cl)Cl>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:16](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([F:14])([F:25])[F:26])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: FC(F)(F)C(Cl)=Nc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)C(=Nc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH (3.47 g, 145 mmol, 60% in mineral oil) in THF (200 mL) was added diethyl malonate (18.5 g, 116 mmol) at 0° C. The mixture was stirred for 30 min at this temperature and 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g, 92 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2Cl2, washed with saturated sodium bicarbonate solution and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to provide 2-(2,2,2-trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester, which was used directly in the next step without further purification.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].N1CCOCC1.C(O)(=O)C(O)=O.[CH3:69][N:70]([CH3:81])[CH2:71][CH2:72][N:73]1[C:79](=[O:80])[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:76]1[CH2:77][CH2:78][C:79](=[O:80])[N:73]([CH2:72][CH2:71][N:70]([CH3:81])[CH3:69])[CH2:74][CH2:75]1)(=[O:54])=[O:55]
Reactant: CN(C)CCN1CCNCCC1=O
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: C1COCCN1
Product: CN(C)CCN1CCN(S(=O)(=O)c2c(C(N)=O)[nH]c3ccc(Br)cc23)CCC1=O

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 4-[2-(dimethylamino)ethyl]-1,4-diazepan-5-one oxalate, the title compound was obtained as a white solid. HRMS (ES) exact mass calculated for C18H25BrN5O4S (M+H+): 486.0805. Found 486.0801.