Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](=[O:22])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])C(OC)=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Cl-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9](=[O:22])[CH2:10][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)c1ncc(F)cc1F)c1ccccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1F)c1ncc(F)cc1F
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
11.65 g (37.67 mmol) of the compound from Example 13A were initially charged in DMSO (37 ml). Subsequently, 2.42 g (41.44 mmol) of sodium chloride and water (7 ml) were added, and the mixture was stirred in a microwave at 150° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed three times with water and once with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. This gave 9.07 g (89%, 85% of theory) of the desired compound in solid form, which was converted without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.Cl.[OH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:38]4[CH2:39][CH:36]([OH:35])[CH2:37]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CC(O)C4)c3)n2)n1
Yield: 55.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.200 g, 0.409 mmol) by treatment with commercially available 3-hydroxyazetidine hydrochloride [CAS-no. 18621-18-6](0.224 mg, 2.05 mmol) and triethylamine (0.57 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.120 g, 55%) as a white solid. MS (ISP) 526.3 [(M+H)+]; mp 205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O1CCCC1.O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-(4-aminophenyl)quinazoline-4-carboxylate (300 mg, 1.02 mmol, 1.00 equiv), LiOH (85 mg, 3.55 mmol, 2.00 equiv), tetrahydrofuran (5 mL) and water (5 mL). The resulting solution was stirred for 2 h at room temperature. To this was added 122.4 mg of acetic acid. The resulting solution was concentrated under vacuum. This resulted in 25.3 mg (9%) of 2-(4-aminophenyl)quinazoline-4-carboxylic acid as a yellow solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:16]([CH3:28])[CH2:17][C:18]2[N:19]([CH3:27])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:8][CH:7]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:28][N:16]([CH2:17][C:18]1[N:19]([CH3:27])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:15])/[CH:13]=[CH:12]/[C:9]1[CH:10]=[N:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 120 h
Yield: 43.4 %

Procedure:
Methyl isocyanate (0.18 mL, 3.05 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.20 g, 0.61 mmole) and triethylamine (0.17 mL, 1.22 mmole) in DMF (20 mL) at RT. The reaction was stirred for 5 days, then was concentrated in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (0.10 g, 43%) as an off white solid: MS (ES) m/e 378 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[N:16]=[C:17]([S:26][CH3:27])[N:18]=[N:19][C:20]=3[C:21](OCC)=[O:22])[CH:12]=2)[NH:7][CH:6]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[N:16]=[C:17]([S:26][CH3:27])[N:18]=[N:19][C:20]=3[C:21]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:22])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2[nH]cc(CCN(C)C)c2c1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CSc1nnc(C(=O)NCc2ccccc2)c(Nc2ccc3[nH]cc(CCN(C)C)c3c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To a stirred mixture of 3-(2-dimethylaminoethyl)-5-(6-ethoxycarbonyl-3-methylthio-1,2,4-triazin-5-ylamino)-1H-indole (0.25 g, 0.62 mmol) in methylene chloride (5 mL) at room temperature under nitrogen was added dropwise benzylamine (0.14 mL, 1.25 mmol, 2.0 eq). The resulting reaction mixture was stirred at room temperature under nitrogen for 48 hours, and then filtered. The resulting yellow solid was recrystallized from methanol: ethyl acetate (4:1) to afford the title compound (0.063 g, 22%) as a yellow solid: mp, 207.0°-209.0° C.; FAB HRMS calculated for [C24H27N7OS.H+ ]482.2079, found 462.2054. Anal. calcd. for C24H27N7OS.3/4 H2O: C, 60.67; H, 6.05; N, 20.63. Found: C, 60.58; H, 5.73; N, 20.58.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1ccccc1F
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of 2-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 736 mg of the product 384.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C=CC(Cl)=CC1=2)=[N+](C)C)C.[NH2:51][C:52]1[C:53]([CH3:67])=[C:54]([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:55]=[CH:56][CH:57]=1>CN(C=O)C.N1C=CC=CC=1>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])=[CH:12][CH:11]=2)[C:7]([NH:51][C:52]2[C:53]([CH3:67])=[C:54]([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:64])([CH3:66])[CH3:65])=[O:61])[CH:55]=[CH:56][CH:57]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Reactant: O=C(O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.5 g (20.6 mmol) of (+/−)-2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)acetic acid were dissolved in a mixture of 170 ml of DMF and 68 ml of pyridine, and 10.2 g (26.8 mmol) of TCTU were added. After 30 min of stirring at room temperature, 4.86 g (20.6 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate were added. After stirring at room temperature overnight, the reaction mixture was concentrated and the residue pre-purified by flash chromatography on silica gel (mobile phase dichloromethane/methanol 100:1). The product obtained in this manner was triturated successively with ethanol and methanol, and the solid was filtered off with suction and dried under high vacuum. This gave 8.5 g (71% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: N#Cc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-[(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]nicotinonitrile was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 6-chloronicotinonitrile (118 mg, 0.85 mmol) in a similar manner as described in Example 22 to give 6.5 mg (6%) of a light brown solid. 1H-NMR (DMSO-d6): δ 10.95 (s, 1H), 8.36 (s, 1H), 7.79 (d, 1H), 7.64 (dd, 1H), 7.57 (d, 1H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.62 (d, 1H), 5.40-5.35 (m, 1H), 2.70-2.55 (m, 2H), 2.07-1.78 (m, 4H); MS m/z (M−1) 365, 367.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([O:22][CH:23]([CH3:25])[CH3:24])=[C:16]([C:19](O)=[O:20])[S:17][CH:18]=1.[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.Cl>O1CCCC1>[Br:13][C:14]1[C:15]([O:22][CH:23]([CH3:25])[CH3:24])=[C:16]([C:19]([NH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[O:20])[S:17][CH:18]=1
Reactant: CC(C)Oc1c(Br)csc1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)csc1C(=O)Nc1nnn[nH]1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
1,1'-Carbonyldiimidazole (2.2 g, 14 mmoles) is added to a solution of 4-bromo-3-(1-methylethoxy)-2-thiophenecarboxylic acid (3.5 g, 13 mmoles) in tetrahydrofuran (50 mL) under argon. The mixture is stirred and heated under reflux for 1.5 hours. 5-Aminotetrazole (1.1 g, 13 mmoles) is added, and heating under reflux continued for 2.5 additional hours. The mixture is then stirred into ice water (200 mL) and acidified with concentrated HCl. After 1 hour the precipitate is filtered off, rinsed with water and dried to afford the product (4.1 g); mp 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][NH:23][CH:24]=1)=[CH:16][CH:15]=3.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2[C:35](=CC=CC=2)[O:34][CH2:33]1.COCBr>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][N:23]([CH2:33][O:34][CH3:35])[CH:24]=1)=[CH:16][CH:15]=3
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4c[nH]nn4)ccc3n(C)c21
Agent: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 mg (0.49 mmol) of compound from Example 47, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-[1,2,3]triazol-4-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 30 mg (0.74 mmol) of 60% NaH and a spatula tip of dibenzo-18-crown-6 are added. 80 μl of bromomethyl methyl ether are then added. The mixture is stirred at ambient temperature for 16 hours. The reaction medium is poured into water and then extracted with EtOAc and the organic phase is dried over MgSO4, filtered and evaporated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with a gradient of EtOAc/50% cyclohexane, then with EtOAc/40% cyclohexane and, finally, 100% EtOAc. The residue is triturated in MeOH so as to obtain a beige solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)([OH:3])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCCl.C(Cl)(Cl)Cl>[O:3]=[C:1]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(CCCC(=O)O)c[nH]c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c3c([nH]c2c1)C(=O)CCC3
Yield: 44.8 %

Procedure:
A mixture or methyl 3-(3-carboxypropyl)indole-6-carboxylate (173 mg), triphenylphosphine (191 mg) and carbon tetrachloride (1.0 ml) in 1,2-dichloroethane (10 ml) was heated at 80° C. for 2 hours. The resulting mixture was diluted with chloroform and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel thin layer chromatography with a mixture of hexane and ethyl acetate (4:1) and recrystallized from a mixture of hexane and ethyl acetate to give methyl 8-oxo-5,6,7,8-tetrahydrocarbazole-2-carboxylate (72.2 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:25][OH:26])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([O:54][C:55](=[O:68])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:25][O:26][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][CH2:59][CH2:58][CH2:57][NH:56][C:55]([O:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:68])=[CH:66][CH:65]=1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 336 h
Yield: 64.7 %

Procedure:
Commercially available N-trityl-L-serine methyl ester (1.60 g, 5.34 mmol) was combined with triphenylphosphine (1.28 g, 4.88 mmol) and [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (2.0 g, 6.68 mmol) in benzene (40 mL) at room temperature. Diisopropyl azodicarboxylate (0.958 mL, 4.86 mmol) was added dropwise and the reaction was stirred for 14 days. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, eluent: 6:1, v/v dichloromethane/ethyl acetate) to provide compound 10 (2.22 g, 51%). 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 6H), 7.39-7.14 (m, 14H), 7.06 (d, 2H), 6.79 (d, 2H), 5.09 (s, 2H), 4.72 (m, 1H), 4.24 (m, 1H), 4.01 (m, 1H), 3.72 (m, 1H), 3.22 (s, 3H), 3.18 (m, 2H), 2.88 (d, 1H), 2.57 (m, 2H), 1.66-1.48 (m, 4H). Rf=0.91 (5:1 v/v dichloromethane/ethyl acetate).
Reaction SMILES: C(O[C:4]1[CH:14]=[CH:13][C:7]([C:8]([CH2:10][C:11]#[N:12])=O)=[CH:6][CH:5]=1)C.O.[NH2:16][NH2:17].[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[NH:17][N:16]=[C:11]([NH2:12])[CH:10]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: NN
Reactant: CCOc1ccc(C(=O)CC#N)cc1
Reactant: CCO
Solvent: O
Product: CCOc1ccc(-c2cc(N)n[nH]2)cc1
Yield: 71 %

Procedure:
A (21.1 g, 112 mmole) portion of p-ethoxy-benzoylacetonitrile from Part A hereinabove and hydrazine monohydrate (7.0 mL, 144 mmole) were combined in 95% ethanol (145 mL) and refluxed for two hours. After cooling, the solvent was evaporated under vacuum and the crystalline residue recrystallized from ethyl acetate (500 mL) to afford 16.14 g (71%) of the subtitled compound as fine white needles (m.p. 152°-156°). An analytical sample was prepared with a second recrystallization (m.p. 155°-157°). 1H NMR (DMSO d6, δ) 7.57 (d, 2H, J=9 Hz, o-phenyl), 6.93 (d, 2H, J=9 Hz, m-phenyl), 5.70 (bs, 1H, pyrazole N-H), 4.35 (bs, 2H, NH2), 4.03 (q, 2H, J=7 Hz), 1.34 (t, 3H, J=7 Hz); IR (mull) 3397, 3136, 1615; 1519, 1474 cm-1 ; UV (ethanol) λ-max(ε) 205(25000), 261(20500); MS m/e(rel. intens.) 203 (M+, 100), 175, (90), 146 (35); Analysis calc'd for C11H13N3O=C, 65.01; H, 6.45; N, 20.67; found=C, 64.73; H, 6.77; N, 20.59; TLC (silica, 15% MeOH/CHCl3) Rf=0.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:14][CH3:15])[CH:4]=1.C(Cl)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:26]Cl>>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:9][C:7]2=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1cc(OC)c(OC)cc1C(N)=O
Reactant: ClCCl
Product: COc1cc2c(=O)nc(-c3ccccc3)n(C)c2cc1OC
Reaction time: 1.5 h

Procedure:
2.00 g (9.51 mmol) 4,5-Dimethoxy-2-methylamino-benzamide were dissolved in 20 ml dichloromethane and 4.01 g (3.31 ml, 28.5 mmol) benzoyl chloride are added. The mixture was boiled for 90 min. After filtration the residue was dissolved in trichloromethane and saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (6.36 g, 32.9 mmol) and 2,6-dichlorobenzothiazole (5 g, 24.5 mmol) in isopropanol (150 mL) was added 4 N HCl in 1,4-dioxane (4 mL, 16 mmol). The mixture was refluxed at 100° C. for 7 h, and then allowed to cool to room temperature. White precipitates formed during cooling were isolated by filtration to yield the first crop of the title compound as a white solid (3.13 g). The filtrate was concentrated in vacuo and then stirred in a mixed solvent of TEA (20 mL) and CH2Cl2 (20 mL) overnight. The solvent was removed in vacuo, and the residue was triturated with isopropanol/ethyl acetate. The isolated white solid was stirred in a mixed solvent of isopropanol (12 mL) and ethyl acetate (8 mL) for 0.5 h and collected by filtration to yield the second crop of the title compound (3.5 g) (total 6.63 g, 85% yield). HPLC/MS (Method C): retention time=2.51 min, [M+H]+=305.3. 1H NMR (500 MHz, DMSO-d6) δ 11.08 (bs, 1H), 7.98 (d, J=2.20 Hz, 1H), 7.94 (m, 2H), 7.88 (m, 2H), 7.64 (d, J=8.25 Hz, 1H), 7.36 (dd, J=8.80, 2.20 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH3:8])O[CH:4]=[C:3]1[O:9][CH2:10][C:11]([O:13]CC)=[O:12].[NH3:16]>>[OH2:1].[OH2:1].[O:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[NH:16][CH:4]=[C:3]1[O:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)COc1coc(C)cc1=O
Reactant: N
Product: Cc1cc(=O)c(OCC(=O)O)c[nH]1
Product: O
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetate (6.36 g) and conc. ammonia (30 ml) was heated at 120° C. for 10 hours. The reaction mixture was concentrated, and water (50 ml) was added to the residue. The resultant aqueous mixture was adjusted to pH 2 to 3 with 10% hydrochloric acid. The resulting precipitates were collected by filtration and washed with wate to give crystals (4.5 g) of 2-(4-oxo-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate, mp 235° to 236° C. (dec.).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:12]=[C:13]([C@H:19]2[NH:23][C@@H:22]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:21][CH2:20]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].N1C=CC=CC=1>O>[CH3:26][C:24]1([CH3:25])[C@H:22]2[CH2:21][CH2:20][C@@H:19]([C:13]3[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=3)[N:23]2[C:2](=[O:3])[C:1](=[O:5])[O:27]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=O)N2[C@H](c3cc(F)c(F)c(F)c3)CC[C@@H]21

Procedure:
Under ice-cooling, oxalyl chloride (320 μL) was added dropwise into a dichloromethane (30 mL) solution containing 2-[(2R,5S)-5-(3,4,5-trifluorophenyl)pyrrolidine-2-yl]propan-2-ol (745 mg) and pyridine (5 mL). After stirring for 30 minutes at the same temperature, water was added to the reaction solution, and the organic layer was partitioned. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (580 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH3:21][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([CH2:33][CH2:34][CH3:35])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1
Reactant: COC(=O)Cc1c(C)nc(N(C)C)nc1-c1ccccc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N(C)C)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A solution of methyl 2-(2-(dimethylamino)-4-methyl-6-phenylpyrimidin-5-yl)acetate (750 mg; 2.63 mmol) in dry DMF (13 mL) was cooled to −15° C. LHMDS (2.89 mL, 2.89 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.385 mL; 3.94 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 680 mg (79%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.46-7.40 (5H, m); 3.82 (1H, dd, J=6.1, 8.2 Hz); 3.69 (3H, s); 3.19 (6H, s); 2.31 (3H, s); 2.08-1.96 (1H, m); 1.62-1.47 (1H, m); 1.02-0.92 (2H, m); 0.65 (3H, t, J=7.1 Hz).