Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:6][C:7]#[N:8].Cl[CH2:16][C:17]#[N:18].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[Se:1][C:16]=1[C:17]#[N:18]
Reactant: N#CCCl
Reactant: [Se-2]
Reactant: N#CC=C(Cl)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1[se]c(-c2ccccc2)cc1N
Temperature: 65 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a suspension of sodium selenide (4.62 g, 36.7 mmol, prepared from 2.9 g of selenium as described above) in DMF (37 mL) was added a solution of 3-chloro-3-phenylprop-2-enenitrile (6.0 g, 36.7 mmol) in DMF (14 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (2.32 mL, 36.7 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (2.0 g, 36.7 mmol) in dry methanol (23 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 15 min. The precipitated solid was filtered and washed with water. The solid was recrystallized from chloroform-hexane to give the product as a brown color solid (4.8 g, 53%), mp 162-164° C. (decomp). 1H NMR (400 MHz, CDCl3): δ 7.46-7.49 (2H, m, Ar—H), 7.37-7.39 (3H, m, Ar—H), 7.01 (1H, s, H-4), 4.55 (2H, br s, —NH2).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCCN(C)CC3)s2)c(C)[nH]c1=O
Product: Cl

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-methyl-1,4-diazepane as described in Steps 5 and 6, Example 1 to give the title compound. MS: m/e 396 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH:28]4[CH2:30][CH2:29]4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH:28]1([C:24]2[CH:25]=[C:26]([CH3:27])[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[C@H:32]([CH3:31])[CH2:36][O:35][C:34]5=[O:37])=[CH:7][C:6]=4[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]3)=[N:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2NS(C)(=O)=O)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2NS(C)(=O)=O)CC1
Yield: 14 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using N-{5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (247 mg) described in Preparation Example 124 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (35.9 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 160 mg (0.72 mmol, 1.1 equiv) of 1-bromomethylnaphthalene in 3 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 385 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.01 (d, 1H, J=8.0), 7.80 (d, 1H, J=7.4), 7.69 (d, 1H, J=8.0), 7.50-6.94 (m, 16H), 6.84 (dd, 1H, J=1.5, 8.3), 5.04 (m, 1H), 4.36 (d, 1H, J=16.4), 4.17 (d, 1H, J=16.4), 3.92 (m, 2H), 3.85 (s, 3H), 3.82 (m, 1H), 1.09 (t, 6H, J=7.1); low resolution MS (FAB)m/e 598 (MH+), 597 (M+), 433.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(NC(C)C)(C)C.[Li].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:22][C:23]1[C:24]([C:25]([NH:1][C:2]2[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=2[C:8]([F:9])([F:11])[F:10])=[O:26])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
To a cooled (-78° C.) solution of 2.1 g of the 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 ml of THF was added dropwise over 3 min. 7 ml of lithium diisopropylamine (LDA, 1.5M in cyclohexane). The mixture was stirred 5 min., and 0.9 g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 min. After 5 min. an additional 3 ml of LDA solution was added followed by an additional 0.5 g of the acid chloride in 1 ml of THF. The resulting mixture was stirred 10 min. and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase was extracted with water and the combined aqueous phases extracted with methylene chloride, dried (magnesium sulfate), filtered and evaporated to give the crude product. This was washed with a small amount of ethyl acetate and dried to give 1.3 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].N1C(C)=CC=CC=1C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC[C@@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl [(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (7.0 g) in methylene chloride (110 ml) were added 2,6-lutidine (4.11 ml) and benzyl chloroformate (5.03 ml) at 0° C. and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was diluted with ethyl acetate (800 ml) and the solution was washed with diluted hydrochloric acid, brine, aqueous saturated sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with a mixture of methylene chloride and ethyl acetate (20:1-4:1) to give methyl [(3R,4R)-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (10.7 g) as an oil.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2]1.[Na].C1OC1.[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19]>C[O-].[Na+]>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][O:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC1CO1
Reactant: CCCCO
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CO1
Product: CCCCCCCCC(O)COCCCC

Procedure:
As described in Example 1, 1 mol of 1,2-epoxydecane was caused to react with 5 times the molar quantity of n-butanol and 0.04 gm-atom of sodium. After distillation of the excess alcohol, the reaction with 10 mols of ethylene oxide was conducted in an autoclave under the conditions described in Example 1, except for the addition of the sodium methylate catalyst. The product thus obtained had a cloud point of 64°C.
Reaction SMILES: [ClH:1].[Cl:2]C[C:4]1[C:5]([CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([O:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([CH3:10])=[N:8][CH:9]=1.[NH2:24][C:25]([NH2:27])=[S:26].[CH:28](O)(C)C>>[ClH:2].[ClH:1].[CH2:15]([O:14][C:12]([O:11][C:6]1([CH2:28][NH:24][C:25](=[NH:27])[SH:26])[C:5]([CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:9]=[N:8][CH:7]1[CH3:10])=[O:13])[CH3:16]
Reactant: CC(C)O
Reactant: NC(N)=S
Reactant: CCOC(=O)OCc1c(CCl)cnc(C)c1OC(=O)OCC
Agent: Cl
Product: CCOC(=O)OCC1=CC=NC(C)C1(CNC(=N)S)OC(=O)OCC

Procedure:
A mixture of 0.1 mole of 5-chloromethyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-2-methylpyridine hydrochloride, 0.11 mole of thiourea are refluxed 2 hours in 100 ml. isopropanol. The reaction mixuture is cooled and 3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-3-isothioureidomethyl-2-methylpyridine dihydrochloride is separated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=O)=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([CH2:17][C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Product: Clc1ccc(Cc2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 200 °C

Procedure:
142.5 g (1 mol) of 4-chloro-o-phenylenediamine, 170.5 g (1 mol) of 4-chlorophenylacetic acid, and 190 g (1 mol) of p-toluene sulfonic acid monohydrate (hereinafter called PTS) were thoroughly blended and heated using a mantle heater while stirring. The temperature was raised to 200° C. in 30 minutes, then the mixture was heated at 200° to 220° C. for 3 hours until almost all steam was evaporated. The reaction mixture thus obtained was poured into aqueous ammonia and stirred to solidify. The solid was washed with water and dried to produce a purple powder. This powder was recrystallized with a solvent to obtain 0.5 g of white, needle-shaped crystals of 6-chloro-2-(4-chlorophenylmethyl)benzimidazole. The compound was dissolved in as much an amount of acetic acid as can dissolve this compound. The solution thus obtained was added to 100 ml of water containing 0.04 g of cupric chloride to obtain the composition of the present invention.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 100.2 %

Procedure:
To a solution of 6.65 g (23 mmol) of N-tert-butoxycarbonyl-O-(4-pentenyl)-L-serine, methyl ester in 500 mL of tetrahydrofuran at room temperature was added a solution of 1.95 g (46 mmol) of lithium hydroxide monohydrate in 100 mL of water. The resulting mixture was stirred at room temperature for 40 hours. To the reaction mixture then was added 46 mL of 1.00N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water (3×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 6.30 g of N-tert-butoxycarbonyl-O-(4-pentenyl)-L-serine as a colorless oil. NMR (300 MHz, CDCl3): δ 5.77 (d of d of t, 1H, J=17.2, 10.2, 6.6 Hz), 5.37 (br d, 1H, J=8.0 Hz), 5.03-4.92 (m, 2H), 4.42 (m, 1H), 3.87 (d of d, 1H, J=9.5, 2.6 Hz), 3.63 (d of d, 1H, J=9.5, 4.0 Hz), 3.45 (t, 2H, J=6.6 Hz), 2.07 (quart., 2H, J=7.3 Hz), 1.64 (quint., 2H, J=7.3 Hz), 1.44 (s, 9H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:29][CH2:30][CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][CH2:30][NH:29][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[CH:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)NCCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow solid, MS (ESI+): m/z=418.3 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC(OC)(C)C.[CH3:13][O:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[CH:18]=[C:17]([CH3:24])[N:16]=1>CC(OC)(C)C.C1COCC1>[CH3:13][O:14][C:15]1[C:20]([CH2:21][NH2:22])=[C:19]([CH3:23])[CH:18]=[C:17]([CH3:24])[N:16]=1
Reactant: COc1nc(C)cc(C)c1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1nc(C)cc(C)c1CN
Temperature: 25 °C

Procedure:
LiAlH4 (48.0 g, 1.27 mol) was added into MTBE (600 mL) portion-wise at room temperature. To the suspension was added 2-methoxy-4,6-dimethylpyridine-3-carbonitrile (Cpd S, 103 g, 0.636 mol) in MTBE/THF (1:1, 600 mL) portion-wise. The reaction mixture was stirred at room temperature for an hour then quenched with water (75 mL). The precipitate was collected by filtration and the solids washed with THF (3×100 mL). The filtrate was concentrated under vacuum to give the 1-(2-methoxy-4,6-dimethylpyridin-3-yl)methanamine (Cpd T), which was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O)(C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].O[C:31]1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([F:19])[CH:21]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](O)[C@@H](NC1(C)C=CC(C#N)=C(Cl)C1)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Reactant: NNC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(F)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOST) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%); 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: OCc1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4ccc(CO)cc4C3)c(F)cc2c1=O
Yield: 22.3 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 5-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(5- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1Cl
Solvent: C1CCOC1
Product: Cc1cc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)ccc1Cl
Yield: 37.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-106, 0.300 g, 0.859 mmol), pivaloyl chloride (0.130 g, 1.03 mmol), TEA (2.0 mL), dry THF (5 mL) to afford 0.140 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 2.37 (s, 3H), 4.29 (d, J=5.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.58 (s, 2H), 7.70 (br d, 1H), 7.91 (s, 1H), 8.20 (d, J=6.0 Hz, 1H), 12.56 (s, 1H); MS (m/z): 433.38 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25]C)([CH3:17])[CH3:16])[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]([C:28]([F:31])([F:29])[F:30])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[OH:25])([CH3:17])[CH3:16])[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2cccnc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1cccc2cccnc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h
Yield: 97.8 %

Procedure:
200 mg (0.46 mmol) of 1-(quinolin-8-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 20 ml of CH2Cl2 is mixed at 0° C. with 9 ml of 1 M boron tribromide-CH2Cl2 solution. After 20 hours at room temperature, the batch is poured into saturated NaHCO3 solution, stirred for 20 minutes and extracted with CH2Cl2. The combined organic extracts are washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Chromatography with hexane-ethyl acetate (0-25%) on silica gel yields 190 mg of the product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1O
Reactant: CCOC(=O)NC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CNC(=O)Oc1ccccc1OC(C)C

Procedure:
To a solution of 2-isopropoxyphenol (1.52 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in dichloroethane (10 ml, was added phosphoryl chloride (1.54 g, 0.01 mole) and refluxed for six hours. The reaction mixture was worked up as described earlier to give 2-isopropoxyphenyl N-methylcarbamate of the formula (VI) as a solid, crystallised from pet. ether, m.p. 89° C. to 90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CCOc1ccnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 23.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-ethoxyquinolin-8-amine (Intermediate-56, 80 mg, 0.425 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 159 mg, 0.553 mmol), oxalyl chloride (162 mg, 1.27 mmol), DMF (1 drop) and DIPEA (219 mg, 1.7 mmol) in CH2Cl2 (2 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.71-8.68 (m, 2H), 8.13 (t, 1H), 7.93-7.90 (dd, J=1.2, 8.4 Hz, 1H), 7.61-7.57 (t, J=8.0 Hz, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.36-7.23 (t, J=8.0 Hz, 1H), 7.12-7.11 (d, J=5.2 Hz, 1H), 4.35-4.29 (m, 4H), 1.50-1.47 (t, J=7.2 Hz, 3H), 1.14 (s, 9H); MS (m/z): 458.24 (M+H)+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11]>C(O)(=O)C>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: BrBr
Reactant: Oc1c(F)cccc1F
Solvent: CC(=O)O
Product: Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
Bromine (13.54 g, 0.0846 mol) dissolved in acetic acid (40 mL) was added drop by drop to a cooled solution of 2,6-difluorophenol (20 g, 0.153 mol) in acetic acid (80 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bisulfite solution and then extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 4-bromo-2,6-difluorophenol (21 g) as a yellow liquid. This was employed directly in the next step without further purification.