Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[Br:1][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(C)ccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(CBr)ccc2ccccc12
Yield: 54.2 %

Procedure:
N-Bromosuccinimide (0.748 g) was added to a solution of methyl 2-methylnapthalene-1-carboxylate (0.7 g) in acetonitrile (30 ml) and the mixture was heated to reflux. Benzoyl peroxide (0.093 g) was added and the reaction mixture was heated at reflux for 4 hours. After cooling, ethyl acetate was added and the solution was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 7.5-25% to give methyl 2-bromomethylnaphthalene-1-carboxylate (0.529 g) as a yellow solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1([CH3:13])[C:9]([O:11][CH3:12])=[O:10].CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[C:4]([CH3:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:5]2)=[N:28][CH:29]=1
Reactant: COC(=O)C1(C)CNCCC1O
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)CN(c2ncc(Br)cn2)CCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-piperidine-3-carboxylate hydrochloride (0.4 g, 1.91 mmol) in EtOH (10 mL) was added DIPEA (1.7 mL, 9.55 mmol) at rt. The resulted mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.37 g, 1.91 mmol). The reaction mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel by using 25% EtOAc: hexane to obtain the product as an off white solid (0.345 g, 55%). MS: 330.12 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([OH:26])(=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>CCOC(C)=O>[CH:7]([O:26][C:16](=[O:25])[C@@H:17]([OH:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of diphenyldiazomethane (0.528 g, 2.719 mmol) in EtOAc (5 mL) was added portionwise with cooling (ice bath) and stirring to a solution of (S)-mandelic acid (0.500 g, 3.286 mmol) in EtOAc (5 mL). The purple reaction mixture was stirred at room temperature for 1 h and was then washed successively with saturated NaHCO3 (3×5 mL) and brine (2×5 mL), dried over anhydrous MgSO4 and evaporated to 0.9864 g of a yellow solid, which was recrystallized from hexanes to give 0.67 g (80%) of 2g. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 3.4515 (d, 1H, OH), 5.2782 (d, 1H, CHOH), 6.75 (s, 1H, CHPh2), 7.20-7.45 (m, 15H, ArH).
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[Na+].S(=O)(=O)(O)O>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
An aqueous solution of disodium terephthalate, passed through adsorption tower (4), was transferred to neutralization tank (5). Then, the solution was stirred by agitator (5a) in neutralization tank and added slowly with 97% sulfuric acid and incessantly until the pH of solution became 4.0. As a result of monitoring by SEM, the particle size of terephthalic acid formed from said neutralization process, its particle size (10 to 20 μm) was very small.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[N:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[CH3:1][S:2]([CH:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[CH:7][CH:6]=1)[CH3:4])=[N:17][C:16]#[N:15]
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Agent: CC(c1ccc(C(Cl)(Cl)Cl)nc1)/S(C)=N/C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(c1ccc(C(Cl)(Cl)Cl)nc1)S(C)=NC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3 mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C. was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 2 hr. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 50% acetone in hexane to give 0.254 g of (1E)-methyl{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}-λ4-sulfanylidenecyanamide (C) as an off-white solid in 40% yield. 1H NMR for the diastereomeric mixture (300 MHz, d6-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H), 4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])=[CH:5][N:6]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])=[CH:5][N:6]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1cnc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 262A (0.040 g, 0.082 mmol) in tetrahydrofuran (1.7 mL) and methanol (0.007 mL, 0.164 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.064 mL, 0.128 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.22 (m, 2 H) 6.38 (t, J=6.25 Hz, 1 H) 7.07 (t, J=7.54 Hz, 1 H) 7.28 (t, J=8.09 Hz, 2 H) 7.59 (m, 5 H) 8.08 (dd, J=8.09, 1.47 Hz, 1 H) 16.19 (s, 1 H). MS (ESI−) m/z 486 (M−H)−.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:20][CH2:21][C:22]([OH:24])=O.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:42])C>C(Cl)(Cl)Cl>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22](=[O:24])[CH:21]([OH:42])[CH3:20])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCO
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(O)C(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
240 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine was dissolved in 4.5 ml of chloroform, and a solution of 144 mg of 3-hydroxypropionic acid in 0.5 ml of ethanol was added, followed by further addition of 300 mg of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 6 hours, and the solvent was distilled off under reduced pressure. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 180 mg of N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl]hydroxypropionamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([O:20][CH3:21])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]>C(OCC)(=O)C.N1C=CC=CC=1.O>[NH2:17][C:15]1[C:14]([O:20][CH3:21])=[CH:13][C:3]([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[C:2]([Cl:1])[CH:16]=1
Reactant: COc1cc(C(=O)Nc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2ccccc2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stannous chloride (334 mg, 1.76 mmol) was added to a solution of 2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide (180 mg, 0.59 mmol) in a mixture of ethyl acetate and ethanol (1/1, 8 mL) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was partitioned between ethyl acetate (50 mL) and an aqueous solution of potassium carbonate (5%, 30 mL); the organic layer was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporate under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 70/30) to give 82 mf of 4-amino-2-chloro-5-methoxy-N-phenyl-benzamide as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:47]1[C:52](=[O:53])[CH2:51][CH2:50][C:48]1=[O:49])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][N:47]2[C:52](=[O:53])[CH2:51][CH2:50][C:48]2=[O:49])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of 5-(9-Carboxy-nonyloxy)-isophthalic acid di-tert-butyl ester (156 mg, 0.34 mmol) in dry THF (2 ml) was added TSTU (125 mg) and DIPEA (0.08 ml). The mixture was stirred under nitrogen over night. The mixture was concentrated. The residue was redissolved in EtOAc and filtered. The filtrate was washed with 0.1N HCl (2×), and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([OH:21])=[O:20])[O:10]1.O[N:23]=[C:24]([NH2:27])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([O:21][N:23]=[C:24]([NH2:27])[CH2:25][CH3:26])=[O:20])[O:10]1
Reactant: CO[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CCC(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(N)=NOC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Oxalyl chloride (4 ml, 46 mmol) was added to a solution of (3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (Justus Liebigs Ann. Chem., 1974, 11, 1856) (5 g, 23 mmol) in dichloromethane (100 ml). The solution was stirred at room temperature for two hours and then the solvent was evaporated under reduced pressure to yield a white solid. This was dissolved in ethyl acetate (80 ml) and N′-hydroxypropanimidamide (2.63 g, 30 mmol) was added followed by N-ethyldiisopropylamine (8.12 ml, 46 mmol). The reaction mixture was stirred at room temperature for 48 hours and then washed with saturated sodium hydrogencarbonate solution (50 ml) and brine (50 ml). The organic layer was separated, dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the product as a dark yellow oil (5.85 g).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH2:8].[N:19]1[N:20]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[N:21]=[CH:22][CH:23]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:20]1[N:21]=[CH:22][CH:23]=[N:19]1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 22; 59 mg, 0.23 mmol), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 51.5 mg, 0.27 mmol), EDC (65.2 mg, 0.34 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (52.4 mg, 0.34 mmol) and triethylamine (0.095 ml, 0.68 mmol) in DCM (2 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (3 ml) and washed with HCl (aq, 1M, 2 ml) then a saturated solution of sodium bicarbonate (2 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2NC(=O)C[S:18]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH3:25][S:26][CH2:27]CCl.[CH3:30][N:31]([CH:33]=[O:34])[CH3:32]>C(OCC)C.Cl>[CH3:3][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:18][CH2:30][N:31]([CH2:32][CH2:25][S:26][CH3:27])[C:33]2=[O:34])[CH:8]=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:4]
Reactant: CN(C)C=O
Reactant: CSCCCl
Reactant: CC(C)(C)c1cc(C=C2NC(=O)CS2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CSCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 100 °C
Reaction time: 144 h

Procedure:
26.7 g of 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinone (i.e., the compound of Example 2) was dissolved in 418 ml of DMF to which was added 3.34 g of a 60% sodium hydride dispersion. The resultant mixture was stirred at 100° C. under an argon atmosphere. To this was added 8.33 ml of methylthioethyl chloride and the resulting black solution was stirred at 100° C. for 6 days. The material was allowed to cool to 30° C. after which insoluble material was filtered off. The solid was washed with DMF until its color was gone leaving a white solid which was discarded. The pH of the filtrate and washings was adjusted to 1.5 by the addition of 1N hydrochloric acid with stirring. The mixture was then diluted with a mixture of 1000 ml of diethyl ether and 500 ml of 1N hydrochloric acid which was then shaken and separated. The organic layer was washed with two portions of water and one portion of brine and subsequently dried over sodium sulfate, filtered, evaporated and chased with chloroform to give a black foam/oil. This material was triturated with about 75 ml of chloroform and then filtered and the insoluble solid was washed with additional chloroform until its brown color was gone. The filtrate was then loaded onto a silica gel column which was eluted with 8000 ml of a gradient of 10-30% ethyl acetate in hexane. The various fractions containing the desired product were combined and again loaded onto a silica gel column and eluted with 8000 ml of a gradient of 10-35% acetone in hexane. The fractions containing the desired product were recrystalled with hexane/ethyl acetate to give 1.2 g of the title compound as a tan/orange solid, m.p. 165.5°-168° C.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20](O)=O)[C@@H:12](O)[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[C:15]1([C:14]2[CH:13]=[CH:9][C:10]([OH:24])=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example 1 but using 0.535 g. of PGF2α, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.385 g. of p-phenylphenol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions, 0.270 g., is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. 114.3°-116.8° C. having Rf 0.25 (TLC on silica gel in ethyl acetate).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[NH:8][N:7]=1)(=[O:4])=[O:3].C(O)C.N>O>[NH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: N
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1n[nH]c2ccc(N)cc12
Yield: 44.2 %

Procedure:
5-Amino-3-methylsulfonylamino-1H-indazole can be obtained as described in Example 4 from 256 mg of 3-methylsulfonylamino-5-nitro-1H-indazole, 10 ml of ethanol, 2 g of ferrous sulfate, 3.2 ml of water and 2.4 ml of 32% aqueous ammonia. 0.1 g of 5-amino-3-methylsulfonylamino-1H-indazole is thus obtained in the form of an oil used as it is in the following step.
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.CO.O>[CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)Cc1ccc(C(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCN(C)Cc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-{[butyl(methyl)amino]methyl}thiophene-2-carboxylate (280 mg, 1.16 mmol) in 2:1:1 dioxane/methanol/water (8.0 mL) is added lithium hydroxide monohydrate (146 mg, 3.38 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the solid residue partitioned between ethyl acetate and water The aqueous phase is acidified to pH 1 with 1 N hydrochloric acid and extracted several times with 3:1 chloroform/2-propanol. The combined organic phase is washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound in pure form. 1H NMR (300 MHz, CD3OD) δ 7.75 (d, J=4 Hz, 1H), 7.41 (d, J=4 Hz, 1H), 4.63 (s, 2H), 3.20–3.14 (m, 2H), 2.85 (s, 3H), 1.82–1.72 (m, 2H), 1.42 (tq, J=8, 7 Hz, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=4[F:37])=[O:25])=[C:19]([F:38])[CH:18]=3)[C:11]([CH2:14][O:15][CH3:16])=[C:12](Br)[N:8]2[N:7]=[CH:6][N:5]=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=4[F:37])=[C:19]([F:38])[CH:18]=3)[C:11]([CH2:14][O:15][CH3:16])=[C:12]([C:49]3[CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:47][CH:48]=3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Intermediate AAC, Step 1) (500 mg, 0.875 mmol, 1.0 eq) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (677 mg, 2.19 mmol, 2.5 eq) followed by 1,4-dioxane (5 mL). Nitrogen was bubbled through the solution for 15 min and then 2M Na2CO3 (6 eq) was added. Nitrogen again bubbled through solution for 15 minutes and [1,1′-Bis(dipheylphosphino)ferrocene] (143 mg, 0.2 eq) was added. N2 was bubbled through the solution for an additional 15 min and then the reaction was placed in a preheated 80° C. oil bath for 17 h. The reaction solution was allowed to cool to rt and was diluted with EtOAc and water. The organic layer was washed water and brine. The combined organic layers were dried (Na2SO4), filtered, condensed, and purified via flash column chromatography (1:1 tetrahydrofuran/hexanes). The purified fractions were collected, evaporated, and left under vacuum overnight to yield the title compound (520 mg, 88.2% yield). 1H-NMR (DMSO-d6) MS [M+H]+=674; LCMS RT=3.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH:27][C:37](=[O:38])[CH2:36][Br:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 66.58 mmol, 1.0 equiv; example 1/step 4) in dichloromethane (250 mL) at 0° C. were slowly added triethylamine (16.84 g, 166.46 mol, 2.5 equiv) and bromoacetyl chloride (20.96 g, 133.17 mol, 2.0 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 2 h at rt. The reaction mixture was cooled again to 0° C., diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over Na2SO4, concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with hexane/ethyl acetate (65:35) to obtain 23.1 g (70%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.40 (s, 9H), 2.92 (br s, 2H), 3.62 (hr s, 1H), 4.03 (d, J=7.1, 2H), 4.30 (s, 2H), 4.72 (d, J=5.1, 2H), 5.24 (dd, J=10.5 Hz, J=1.0, 1H), 5.35 (dd, J=16.6 H, J=0.7, 1H), 5.50 (d, J=7.7 Hz, 1H), 5.98-6.05 (m, 1H), 6.82(d, J=8.8 Hz, 1H), 7.68 (dd, J=8.6 Hz, J=1.5 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H), 9.43 (s, 1H).