Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([O:30]C)=O)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([NH:38][CH3:37])=[O:30])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Product: CNC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1

Procedure:
The title compound was prepared methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate following a procedure analogous to that described in Example 71 Step 3 using methylamine in place of ammonia. LC-MS Method 2 tR=1.055 min, m/z=491.12; 1H NMR (CD3OD) 1.18 (m, 1H), 1.48 (d, 3H), 1.51 (m, 1H), 1.85 (m, 2H), 2.13 (m, 1H), 2.25 (m, 1H), 2.48 (m, 1H), 2.88 (s, 3H), 3.09 (m, 1H), 3.38 (m, 2H), 5.51 (m, 1H), 6.98-7.07 (m, 4H), 7.22 (m, 2H), 7.42 (m, 2H), 8.28 (m, 1H), 8.75 (s, 1H), 8.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[Br:19][C:20]1[CH:21]=[C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])[CH:23]=[CH:24][CH:25]=1>O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:1][C:2]([C:6]3[CH:11]=[CH:10][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:8][CH:7]=3)=[C:3]([C:4]#[N:5])[C:28](=[O:29])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Br)c1
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(-c2cccc(Br)c2)cc1=O
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 3-amino-3-(4-phenoxyphenyl)acrylonitrile (0.553 g, 2342 mmol) and ethyl 3-(3-bromophenyl)-3-oxopropanoate (2.540 g, 9.37 mmol) was microwaved at 230° C. for 20 min. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (100 mL). The ethyl acetate phase was washed with saturated ammonium chloride, brine, dried (MgSO4), and concentrated. Silica gel chromatography, eluting with 0-80% ethyl acetate in hexanes, gave 6-(3-bromophenyl)-4-oxo-2-(4-phenoxyphenyl)-1,4-dihydropyridine-3-carbonitrile as brown solid (0.909 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (1H, br. s), 7.70 (2H, δ, J=8.28 Hz), 7.62 (2H, δ, J=7.28 Hz), 7.35 (3H, t, J=7.40 Hz), 7.18 (1H, t, J=7.28 Hz), 7.03 (4H, dd, J=11.92, 8.66 Hz), 6.68 (1H, br. s); MS (ES+) m/z: 443,445 (M+H); LC retention time: 4.361 min (analytical HPLC Method A).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[C:11](Cl)=[O:12])[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1>>[C:22]1([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11]([CH:4]3[CH:5]4[CH2:10][N:1]5[CH2:8][CH:7]([CH2:9][C@@H:3]3[CH2:2]5)[CH2:6]4)=[O:12])[CH2:16]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C1C2CC3CC1CN(C3)C2
Product: O=C(NC1CCN(CCc2ccccc2)C1)C1C2CC3C[C@@H]1CN(C3)C2

Procedure:
1-Azaadamantane-4-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-azaadamantane-4-carboxamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[C:12]2[CH3:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: CC1C(=O)CCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1c2n(c3ccc(Cl)cc13)C(=O)CCC2
Temperature: 82.5 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a suspension of p-chlorophenylhydrazine hydrochloride (8.52 g) in toluene (100 ml) were added 2-methylcyclohexane-1,3-dione (5.0 g) and 40% sulfuric acid (40 ml), and the mixture was stirred at 80-85° C. for 4 hours. After cooling, the organic layer was separated. The aqueous layer was extracted with toluene. The organic layers were combined and washed with aqueous sodium bicarbonate, water, and brine. After dried over sodium sulfate, the organic layer was evaporated. The residue was recrystallized from methanol to give 2-chloro-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (4.63 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C([Li])CCC.CN(C)[CH:32]=[O:33].Cl>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:3]=1[CH:32]=[O:33]
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)cc2)CC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 46 mmol of 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl in 100 ml of dry tetrahydrofuran is cooled to −75° C., and 50 mmol of n-butyllithium (1.6 M solution in n-hexane) are added dropwise under a protective-gas atmosphere at such a rate that the internal temperature does not exceed −75° C. The mixture is subsequently stirred at this temperature for a further 2 hours. 60 mmol of N,N-dimethylformamide are then likewise added dropwise at such a rate that the internal temperature always remains below −75° C. When the addition is complete, the reaction solution is allowed to thaw slowly and is hydrolysed at −10° C. by transfer of the reaction solution into ice-water. The mixture is acidified using hydrochloric acid (pH=3) and extracted with tert-butyl methyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution and dried using sodium sulfate. After the solvent has been removed under reduced pressure, the crude product is chromatographed on silica gel with dichloromethane/n-heptane 1:1 as eluent, giving 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl-2-carbaldehyde in the form of slightly yellowish crystals; m.p. 62° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:20]=[O:21]
Reactant: OCc1ccc(NCCCCCc2ccccc2)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(NCCCCCc2ccccc2)c(Br)c1

Procedure:
A solution of 5-bromopentylbenzene [14469-83-1](4 g, 17.6 mmol) in HMPA (55 g) was treated with 4-amino-3-bromobenzemethanol [146019-46-7] and dry K2CO3 (4.87 g, 35.2 mmol) for ˜18 h at 120° C. The mixture was cooled to rt, poured onto water (600 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL), dried over Na2SO4, concentrated, and purified by chromatography (ethyl acetate/hexane) to give (3-bromo-4-((5-phenylpentyl)amino)phenyl)methanol (2.24 g, 37%). A solution of (3-bromo-4-((5-phenylpentyl)amino)phenyl)methanol (8.0 g, 23 mmol) in dichloromethane (160 mL) was treated with silica gel (24 g) and PCC (14.9 g, 69 mmol) at rt for ˜18 h. The mixture was concentrated, and purified by chromatography on silica gel (ethyl acetate-hexane) to give 3-bromo-4-((5-phenylpentyl)amino)benzaldehyde Intermediate-21 (3.5 g, 44%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([C:17](OCC)=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:14])[F:15])[CH:10]([CH2:17][OH:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 1.8 g (6 mmol) of 1-benzyl-3-(RS)-carboethoxy-4-(RS)-trifluoromethylpyrrolidine in 20 mL of THF at 0° C. was added 4.8 mL (4.8 mmol) of a 1M solution of LAH in THF and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 5N NaOH solution and extracted with ether. The combined organic fractions were washed with 2N NaOH solution and sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:8) to give 1.5 g of the title compound. 1H NMR (CDCl3) δ (key peaks) 7.28-7.37 (m, 5H), 3.76 (d of d, 1H, J=3.5, 10.5 Hz), 3.63 (s, 2H), 3.62 (d of d, 1H, J=5.0, 10.5 Hz), 3.11 (t, 1H, J=9.0 Hz), 2.60 (t, 1H, J=7.0 Hz), 2.45-2.49 (m, 1H), 2.42 (d of d, 1H, J=7.5, 9.5 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:21])[CH2:14][O:13][C:12]([CH3:20])([C:15](OCC)=[O:16])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>>[CH2:1]([O:8][CH2:9][C:10]1([CH3:21])[CH2:14][O:13][C:12]([CH3:20])([C:15]([NH2:22])=[O:16])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C)OCC(C)(COCc2ccccc2)O1
Reactant: N
Product: CC1(COCc2ccccc2)COC(C)(C(N)=O)O1

Procedure:
Ethyl 4-benzyloxymethyl-2,4-dimethyl-1,3-dioxolan-2-carboxylate (5.0 grams) and concentrated aqueous ammonia solution (50 milliliters, 0.880 S.G.) were stirred together at room temperature for 3 days. The white solid formed was filtered off, washed with water and recrystallised from cyclohexane to give the desired product as an isomer mixture melting point 72°-92° C.
Reaction SMILES: [CH2:1]([P:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[OH:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([P:9]([Cl:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=P(O)(CCc1ccccc1)CCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(Cl)(CCc1ccccc1)CCc1ccccc1

Procedure:
Diphenethylphosphinic acid (1.67 g, 6.1 m mole) was dissolved in carbon tetrachloride (5 ml), and sulfuryl chloride (1.46 g, 10.8 ml) was added thereto, and the mixture was heated while refluxing for 2 hours. It was confirmed that the starting material did not remain by tracement of the NMR spectrum. The solvent and excess sulfuryl chloride were distilled off under reduced pressure to obtain an oily diphenethylphosphinylchloride, which was supplied for the following reaction.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]OS(C)(=O)=O)[CH2:7][CH2:6]1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[H-].[Na+]>CN(C)C=O>[N:30]1([CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][N:2]([CH3:1])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:6][CH2:7]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-methanesulfonic acid 4-{2-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-ethyl}-cyclohexylmethyl ester (example 13.2) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-[2-(4-imidazol-1-ylmethyl-cyclohexyl)-ethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 430 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>CO.C(Cl)(Cl)Cl>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl) thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene (47.1 mg, 11.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg, 0.16 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, a pale brown solid (46 mg, 66% yield), m.p. 172-175° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[C:5]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[C:4]([C:20](=[O:22])[CH3:21])[CH:3]=1.[H][H]>CO.[Pt]>[NH2:9][C:6]1[C:5]([C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[C:4]([C:20](=[O:22])[CH3:21])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cc(F)cc(F)c1

Procedure:
A mixture of 1-(4-chloro-3′,5′-difluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (8.61 g 26.4 mmol) in 160 mL of methanol was hydrogenated in the presence of 0.86 of 5% Pt/C, under ballon pressure of hydrogen, overnight. After filtering off catalyst, the filtrate was concentrated under reduced pressure to give the desired product. LCMS calculated for C15H13ClF2NO (M+H)+: m/z=296.1; Found: 296.1.
Reaction SMILES: [N:1]1([CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([O-:9])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41]>O1CCCC1>[C:10]([CH:6]([N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[C:7]([NH:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41])=[O:9])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COC1(N)C(=O)N2C(C(=O)O)=C(C)CSC21
Reactant: CCOC(=O)C(C(=O)[O-])n1cccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)NC1(OC)C(=O)N2C(C(=O)O)=C(C)CSC21)n1cccc1
Temperature: 0 °C

Procedure:
2-(1-Pyrryl)propanedioic acid, 3-ethyl ester, 1 equivalent and 1 equivalent of triethylamine is added to tetrahydrofuran (THF) which is cooled to 0° C. While stirring, iso-butyl chloroformate, 1 equivalent, is added and the temperature is maintained at 0° C. for about 15 minutes. A cold solution of 7-amino-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1 equivalent, and triethylamine, 1 equivalent, in 50% aqueous THF is added with stirring to the previous solution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1N
Yield: 55.5 %

Procedure:
A mixture of N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (6.0 g), dioxane (150 ml), water (30 ml), sodium hydrosulfite (14.6 g) and sodium hydrogencarbonate (17.6 g) was heated under reflux for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (1/3) as the eluant to afford the title compound (2.98 g). Rf=0.23 (thin-layer chromatography on a silica gel plate using ethyl acetate/n-hexane (1/3) as the eluant).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][O:13][CH2:12]2.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][O:13][CH2:12]3)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: C1CC2COCC1N2
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
In a 250 mL round-bottomed flask was placed 2,4,6-trichloropyrimidine (8, 0.575 mL, 5 mmol) in EtOH (20 mL) to give a colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 748 mg, 5.00 mmol) was added and the solution was cooled to 0° C. Triethylamine (2.091 mL, 15 mmol) was added slowly and the mixture was allowed to slowly warm to room temperature. The mixture was stirred at room temperature for one hour and was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (5-20%) to give the title compound (980 mg, 75%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O.Cl>[NH:12]([C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1)[NH2:13]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NN
Agent: Cl
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Yield: 77 %

Procedure:
6-Chloronicotinic acid (8.0g) was added to 85% hydrazine hydrate (35 ml). The reaction mixture was placed in a 100° C. oil bath for 4 hours. The homogeneous reaction mixture was concentrated to dryness to give a white solid. The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed. The precipitate was isolated by filtration and the solid was washed with 95% ethanol and ether to give 6.0 g of a pale brown solid; yield 77% m.p. 292°-293° C.;
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4nccc(C(F)(F)F)n4)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 87) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereoisomers (401.4 mg, 66%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][S:17][C:18]#[N:19])=[CH:11][CH:10]=1.Cl.[NH2:22][C:23]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]1>C(O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([NH:22][C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[S:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C1(N)CCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CCC1
Temperature: 68 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Triethylamine (3.30 mL, 23.7 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.50 g, 21.6 mmol), prepared in step 1 of Example 1, and ethyl 1-aminocyclobutanecarboxylate hydrochloride (4.24 g, 23.6 mmol) in 130 mL of absolute ethanol. The mixture was then stirred at 68° C. overnight. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 2 N NaOH. The organic layer was separated, washed two times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 45% methylene chloride in hexane to 100% methylene chloride as the eluent gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutane carboxylate (1.0 g, 12%) as a brown oil, MS (ESI) m/z 381 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To 3.2 g (0.0093 mol) of the product from Step A was added 100 mL methanol and 100 mL 1N sodium hydroxide. The reaction mixture was heated at reflux for 18 h, cooled to room temperature, poured into 200 mL water and extracted with ether (1×100 mL). The aqueous phase was acidified with concentrated HCl and extracted with ether (3×100 mL), washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 3.0 g of a yellow solid, mp 157°-158° C.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:25][OH:26]>F[B-](F)(F)F.[Ag+]>[CH3:25][O:26][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: CO
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Yield: 35 %

Procedure:
There were mixed 4.12 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, 9.37 g of silver tetrafluoroborate and 100 ml of methanol. The mixture was refluxed for 4 hours. The reaction mixture was cooled and filtered to remove the insolubles. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 1.27 g (yield: 35%) of 2,3-dihydro-3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.