Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[F:22][C:23]([F:35])([F:34])[C:24]([NH:26][C@H:27]1[C@@H:31]([CH2:32][F:33])[CH2:30][NH:29][CH2:28]1)=[O:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][C@H:31]([CH2:32][F:33])[C@H:27]([NH:26][C:24](=[O:25])[C:23]([F:35])([F:34])[F:22])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: O=C(N[C@@H]1CNC[C@@H]1CF)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1c(F)c(N2C[C@H](CF)[C@H](NC(=O)C(F)(F)F)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 13 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-trifluoroacetylamino-4-fluoromethylpyrrolidine, diisopropylethylamine, and dioxane was refluxed for 12 hours to give 5-amino-7-(cis-3-trifluoroacetylamino4-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: O=c1[nH]c2ccc(NCCCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-amino-2-benzoxazolone (6.00 g) and molecular sieves 4A (10.0 g) in dry benzene (100 ml) was added 3-phenylpropanal (5.25 ml), and then the mixture was stirred at room temperature for 1 hour. Methanol (150 ml) was combined with this and sodium borohydride (1.50 g) was added in portions at room temperature. The reaction mixture was filtered, the filtrate was concentrated and 5% sodium bicarbonate was added. The organic material was extracted with dichloromethane. The dichloromethane phase was separated, washed with brine. Drying and removal of solvent under reduced pressure gave a crude product which was crystallized from hot ethanol to afford 7.07 g of the title compound: mp 129°-130° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>CC(=O)CC>[Br:21][CH2:22][CH2:23][O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: BrCCOc1ccc2c(c1)[nH]c1ccccc12
Reaction time: 28 h

Procedure:
A mixture of 2-hydroxycarbazole (30 g; mfd. by Aldrich), potassium carbonate (113.1 g; mfd. by KANTO CHEMICAL) and 1,2-dibromoethane (211 mL; mfd. by TOKYO KASEI KOGYO) in 2-butanone (165 mL; mfd. by Wako Pure Chemical Industries) was stirred vigorously at a reflux temperature for 28 hours. The reaction solution was poured into water (1050 mL) all at once and stirred. The precipitated crystal obtained by filtration was washed with water (1 L) and 2-propanol (250 mL), and then dried under reduced pressure at room temperature to give the title compound (43.43 g) as a white solid.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[F:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([F:15])[C:10]([F:16])=[C:9](F)[C:8]=1[F:18].C(Cl)(=O)C.O>CC(N(C)C)=O>[F:6][C:7]1[C:8]([F:18])=[C:9]([S:3][C:1](=[O:4])[CH3:2])[C:10]([F:16])=[C:11]([F:15])[C:12]=1[CH:13]=[O:14]
Reactant: CC([O-])=S
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)Sc1c(F)c(F)c(C=O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Potassium thioacetate (1.28 g, 11.2 mmol) was added to a solution of pentafluorobenzaldehyde (1.24 mL, 10.2 mmol) in anhydrous DMA (20 mL). After a strong exotherm subsided, the mixture was stirred at rt for 30 min. Acetyl chloride (1.60 mL, 22.4 mmol) was added and the mixture was stirred for another 30 min, then poured into water and extracted twice with ethyl ether. The combined organic extracts were dried (Na2SO4) and evaporated to obtain an orange oil which was chromatographed (silica, CH2Cl2/hexanes, 2:3) affording a pale-yellow solid. Recrystallization from heptane gave white crystals (1.77 g, 69%). mp 86-87° C.; 1H NMR δ 2.53 (s, 3H), 10.30 (s, 1H); 13C NMR δ 30.9, 115.5, 117.2, 145.3, 148.7, 182.9, 187.9; FAB-MS obsd 252.9936, calcd exact mass 252.9946; Anal. Calcd. for C9H4F4O2S: C, 42.86; H, 1.60; S, 12.72. Found: C, 43.00; H, 1.71; S, 12.67.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:17])([CH2:12][C:13]([F:16])([F:15])[F:14])[N:5]([CH3:18])[C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:18][N:5]1[C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:17])[CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)CC(F)(F)F
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(CC(F)(F)F)N2C
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A flask was charged with 6-bromo-1,2-dimethyl-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (420 mg, 1.22 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.13 g, 3.7 mmol), sodium carbonate (366 mg, 6.1 mmol), 1,2-dimethoxyethane (6 mL) and water (3 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (98 mg, 0.12 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 2 h, 8 M aqueous NaOH (1 mL) was added. After stirring at 100° C. for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/heptane) to give the title compound (212 mg, 50%) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][N:18]=[CH:17][CH:16]=3)[C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2cnccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2cnccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a suspended solution of 3-(2,6-dichloro-3-nitro-phenyl)-1-methyl-1H-[1,6]naphthyridin-2-one (1.55 g, 4.427 mmol) in EtOH (12 mL) is added a solution of Sn(II)Cl2 (3.80 g, 19.92 mmol) in HCl (con. 16 mL) at 75° C. After stirring for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 to a pH of 8. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product. The crude product is purified by recrystallization with CH2Cl2/EtOAc/Hexane to give the titled intermediate as a solid (1.32 g, 93.15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=1.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]([CH3:18])[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 50 ml of fuming nitric acid (90%) was added slowly 8.29 g of 3-(2,5-di-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole. After addition, the mixture was allowed to warm to room temperature and then gently heated to 52° C. Heated for 2.5 hours, then cooled and poured onto ice. The resulting mixture was extracted with ether and the ether then washed twice with water, dried with anhydrous magnesium sulfate, filtered and the solvent removed by concentration in vacuo. The residue was purified utilizing a combination of chromatography and crystallization to give 5.62 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.C(N1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)C.[NH2:31][CH2:32][CH:33]1CCCCO1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[O:28]1[CH2:27][CH2:26][CH:33]([CH2:32][NH:31][C:20]([C:13]2[C:14]([C:16]([F:17])([F:19])[F:18])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:30][CH2:29]1
Reactant: CCN1CCOCC1
Reactant: NCC1CCCCO1
Reactant: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CCOCC1)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Reaction time: 24 h

Procedure:
To a solution of 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (86 g) in dimethylformamide (800 ml) was added successively N-ethylmorpholine (93 ml), 4 aminomethyltetrahydropyran (29.5 g), 1-hydroxybenzotriazole hydrate (51.5 g) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (56.2 g). The solution was stirred for 24 h. Dimethylformamide was partially removed (approx 650 ml) under reduced pressure and 5% sodium bicarbonate solution added (3×500 ml, added portionwise to control the release of carbon dioxide). The mixture was stirred with overhead stirring for 3 h and the resulting solid filtered onto a sinter. The solid was washed with 5% sodium bicarbonate (4×400 ml) and water (3×400 ml) then dried over sodium hydroxide in vacuo at 50° C. to afford the title compound (109.1 g)
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1[C:7]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]2[CH3:33])=[N:8][C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21]C)=[N:10][C:11]=1[CH3:12]>ClCCl>[CH3:5][C:6]1[C:7]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]2[CH3:33])=[N:8][C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[OH:21])=[N:10][C:11]=1[CH3:12]
Reactant: COc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(Nc2ccc(F)cc2O)nc(N2CCc3ccccc3C2C)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
Boron tribromide (1M dichloromethane solution, 1.9 ml, 1.9 mmol) was added dropwise to a solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-methoxyphenylamino)pyrimidine(0.247 g, 0.63 mmol) in dichloromethane(2 ml) at 0° C., stirred for 1 hour, and poured into ice water. The separated organic layer was concentrated and the residual oil was purified by column chromatography (dichloromethane/methanol=10/1) to give 57 mg of the titled compound. (Yield 24%) NMR (CDCl3): 1.5 (d, 3H), 2.2 (s, 3H), 2.3 (s, 3H), 2.7 (m, 1H), 3.1 (m, 1H), 3.5 (m, 1H), 3.9 (m, 1H), 5.0 (q, 1H), 6.6 (m, 6H), 7.0 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:19][C:18]([Cl:21])([Cl:20])[C:17]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)CCO)cc1N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=S(=O)(CCO)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (2.31 mmol) 3,4-diamino-benzene-sulfonylethan-2-ol were dissolved in 10 mL concentrated acetic acid. 0.4 mL (1.4 equiv.) methyl-2,2,2-trichloroacetimidate were added slowly and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with 100 mL toluene and the solvent was removed under reduced pressure. The residue was rinsed with toluene, filtered and dried under vacuo to give a brown crystalline solid pure enough for all further reactions. Yield: 680 mg MS (ES+): m/e=345, chloro pattern.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:15]([NH:32][CH2:33][CH:34]([C:36]([OH:38])=[O:37])[OH:35])([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]([Si:5]([CH3:7])([CH3:6])[O:35][CH:34]([CH2:33][NH:32][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:36]([OH:38])=[O:37])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C(NCC(O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 50 °C
Yield: 96.5 %

Procedure:
TBDMSCl (1.01 g, 6.72 mmol), DMAP (0.19 g, 1.52 mmol) and pyridine (0.97 g, 12.2 mmol) were added to a stirred solution of FMOC-isoserine (1.00 g, 3.05 mmol) in DMF (20 mL). The reaction mixture was heated at 50° C. for 18 hrs. Water (10 mL) was added and the reaction mixture was concentrated in vacuo. DCM and HCl (0.5 M) were added and the two phases were separated. The aqueous phase was extracted two times with DCM. The organic extracts were combined concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 20-100% EtOAc in heptane) to give the title compound (1.3 g). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, 2H), 7.59 (m, 2H), 7.40 (t, 2H), 7.30 (m, 2H), 5.14 (br s, 1H), 4.29 (m, 4H), 3.53 (m, 2H), 0.91 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH2:30]([N:14]1[CH2:15][CH2:16][CH:11]([N:8]2[C:9]3[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:5]=3[CH:6]=[N:7]2)[CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and benzaldehyde (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (27%). LCMS: 548.10 (M+1)+; HPLC: 99.16% (@ 254 nm) (Rt; 5.349); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (s, 1H), 8.59 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.25 (s, 1H), 7.69 (d, 1H, J=1.2 Hz), 7.34 (d, 4H, J=4.4 Hz), 7.27-7.24 (m, 1H), 5.87 (s, 1H), 4.70 (m, 1H), 4.33 (d, 2H, J=4.8 Hz), 3.55 (s, 2H), 2.93 (d, 2H, J=10 Hz), 2.30-2.20 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.S(Cl)([Cl:15])=O.[N:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2>N1C=CC=CC=1>[ClH:15].[N:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[N:20]([C:10]([C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)=[O:12])[CH2:19][CH2:18]2
Reactant: C1CN2CCC(C2)N1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cl
Product: O=C(c1n[nH]c2ccccc12)N1CCN2CCC1C2

Procedure:
A 50 ml reactor is charged with 0.165 g (1.02 mmol) of 1H-indazole-3-carboxylic acid and 1 ml of thionyl chloride and the mixture is heated at ref lux for 1 h 30 min and concentrated under reduced pressure. Then 1.2 ml of pyridine and 0.30 g (2.67 mmol) of 1,4-diazabicyclo[3.2.1]octane are added and the mixture is heated at reflux for 1 h 30 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=O)[C:22](OC)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].Cl.[CH2:30]([NH:32][C:33]([NH2:35])=[NH:34])[CH3:31].[C:36](=O)(O)[O-:37].[Na+].CO>O>[CH3:36][O:37][C:21]1([C:18]2[C:17]3[CH:27]=[C:13]([N:4]4[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]4=[O:28])[CH:14]=[CH:15][C:16]=3[S:20][N:19]=2)[C:22](=[O:23])[NH:35][C:33](=[N:32][CH2:30][CH3:31])[NH:34]1
Reactant: COC(=O)C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=C([O-])O
Reactant: CCNC(=N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN=C1NC(=O)C(OC)(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of methyl 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.0820 g, 1.98 mmol), ethyl guanidine hydrochloride (0.270 g, 2.18 mmol), sodium bicarbonate (0.180 g, 2.14 mmol) and methanol is stirred overnight at reflux, cooled to room temperature and poured into water. The resultant suspension is stirred 20 minutes and filtered with cold water wash to afford the title compound as a white solid (0.610 g, 63.9%, mp 257° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-:16].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:16])[CH2:14][CH2:13][N:12]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CBr
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidine (0.02 g, 0.081 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-2-methylpropane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 303 (M+, 1), 302 (M+, 2), 260 (63), 258 (bp), 242 (19), 240 (29).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[F:24].[ClH:27].Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1.C(NC(=O)OC1C(C)=C2N(C=1)N=CN=C2OC1C=CC(N[C:93]([NH:95][C:96](=[O:105])[CH2:97][C:98]2[CH:103]=[CH:102][C:101]([F:104])=[CH:100][CH:99]=2)=[O:94])=CC=1F)C>>[ClH:27].[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:93]([NH:95][C:96](=[O:105])[CH2:97][C:98]2[CH:103]=[CH:102][C:101]([F:104])=[CH:100][CH:99]=2)=[O:94])=[CH:19][C:18]=1[F:24]
Reactant: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Yield: 13 %

Procedure:
4-(6-(3-(Dimethylamino)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (12 mg, 0.03 mmol) was converted to the title compound (2.5 mg, 13%) in a manner similar to the preparation of Compound E of Example 31, except that 2-(4-fluorophenyl)-acetyl isocyanate (0.10 mL, 0.04 mmol, Compound C of Example 4) was used instead of benzenesulfonyl isocyanate. 1H NMR (CD3OD) δ 10.77 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.40–7.23 (m, 5H), 7.11–7.02 (m, 3 H), 4.15–4.12 (m, 2H), 3.71 (s, 2H), 3.41–3.36 (m, 2H), 2.97 (s, 6H), 2.44 (s, 3H), 2.31–2.22 (m, 2H); HRMS(ESI), 539.2218 (M+H)+ calc, 539.2218 (M+H)+ found.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH3:20])[C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1)C.C(OC(=O)C[C@H]1C2N([C@H](C3C=CC(Cl)=CC=3)C)C3C(=CC(F)=CC=3S(C)(=O)=O)C=2CCC1)C.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([N:17]2[C:18]3[C@@H:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][CH2:8][CH2:9][C:10]=3[C:11]3[C:16]2=[C:15]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:14]=[C:13]([F:32])[CH:12]=3)[CH3:20])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: CCOC(=O)C[C@@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(Cl)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O
Temperature: 0 °C

Procedure:
The diastereomeric mixture of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)-ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate (1 eq) was dissolved in a 3.5/1 mixture of THF/MeOH (0.25M) and cooled at 0° C. Aqueous LiOH 1N (1 eq) was slowly added and the mixture was stirred at 0° C. for 12 h or until almost complete hydrolysis of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate, the other diastereomer was only slightly hydrolyzed under these conditions. AcOH was added and the solvent was removed by evaporation. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and [(1R)-9-[(1S)-1-(4-chloro-phenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid were separated by flash chromatography eluting with 40% EtOAc in hexanes containing 1% AcOH to give the desired [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid with de>90% which was swished in 30% EtOAc in hexane to give the desired compound as a white solid with de>95%.