Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[CH3:20]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH:18]=[CH2:20]
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Reactant: COC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.28 g of methyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature within 1 minute with 962 mg of potassium tert.butylate and stirred for 1 hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.5 g of 4-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]butyraldehyde in 20 ml of tert.butyl methyl ether and stirred at 0° C. for a further 45 minutes. Thereafter, the reaction mixture was diluted with 80 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the crude product (2.1 g) on silica gel at 0.5 bar with ethyl acetate/petroleum ether (vol. 2:98) and recrystallization from 20 ml of methanol gave 1.26 g of trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarbonitrile as colorless crystals with m.p. (C-SB) 20.1° C., SB -N 36.9° C., cl.p. (N-I) 54.8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)[CH:3]=1)#[N:20]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-3-(trifluoromethyl)benzene (66 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from methanol to give the title compound (106 mg, 56%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 94.2 %

Procedure:
To a stirred solution of 2-nitrophenol (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].CO[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]>>[CH3:2][N:3]([CH3:4])[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]
Reactant: CNC
Reactant: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Agent: Cl
Product: CN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from dimethyl amine hydrochloride (278 mg, 3.41 mmol) and 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (150 mg, 0.341 mmol) to give a white solid (74 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 7.27-7.31 (m, 1 H) 7.01-7.13 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4: C, 60.92; H, 5.33; N, 15.44. Found: C, 60.66; H, 5.37; N, 15.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the compound from example 5 (200 mg, 0.53 mmol) in dichloromethane (5 mL) was added triethylamine (110 μL, 0.79 mmol). The reaction was cooled to 0° C. and methanesulfonyl chloride (48.9 μL, 0.63 mmol) was added. The solution was stirred for 1 hour at room temperature and diluted with water (5 mL). The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo and azeotroped with ethyl acetate to give the product as a white crystalline solid, 196 mg (76%).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1([CH3:19])[O:18][CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13][O:12]1>CC(O)C>[CH3:10][C:11]1([CH3:19])[O:18][CH2:17][C@@H:16]([OH:15])[C@H:14]([NH:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:13][O:12]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)OCC2OC2CO1
Solvent: CC(C)O
Product: C[C@H](N[C@@H]1COC(C)(C)OC[C@H]1O)c1ccccc1
Yield: 35 %

Procedure:
The known method by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582 for the preparation of the enantiomer of the title compound was followed. (S)-1-Phenylethanamine (30.4 ml, 236 mmol) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (34 g, 236 mmol) were dissolved in iPrOH (16 ml) and heated under reflux for 16 h. The mixture was stirred and cooled in an ice bath. Hexanes (90 ml) was added. After 1 h the colourless crystalline solid was filtered off, washed with hexanes and dried to give (5S,6R)-2,2-dimethyl-6-((S)-1-phenylethylamino)-1,3-dioxepan-5-ol (21.9 g, 35%). The 1H NMR was in agreement with that described for the enantiomer of the title compound by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582. [α]D 20 −96.6 (c, 1.01, MeOH). Lit. (T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582) [α]D 25 +96.2 (c 1.00, MeOH) for the enantiomer.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][S:12][C:13]2[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][S:12][C:13]2[S:17][C:16]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CSc2ccc(S(N)(=O)=O)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(SCc2ccc(O)cc2)s1
Reaction time: 4 h
Yield: 2.9 %

Procedure:
A solution of boron tribromide (3.12 ml, 8.27g, 0.033 mol) in methylene chloride (30 ml) was added dropwise to a stirred solution of 5-(4-methoxybenzylthio)thiophene-2-sulfonamide (3.4 g, 0.11 mol) in methylene chloride (100 ml). The dark reaction mixture was stirred four hours, treated with water (125 ml) and extracted with ethyl acetate (500 ml). The organic layer was separated, washed with water (2×100 ml), saturated NaCl solution (100 ml) and dried (Na2SO4). The filtrate was evaporated to dryness, the residue slurried with ether and filtered to give 0.95 g off-white solid. Recrystallization from dichloroethane gave material with m.p., 167°-168.5° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[CH2:15][C:16]([O:18]CC1CC1)=[O:17].O>CO>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH:7]=[CH:6][C:5]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(Cc1ccc(OCC2CC2)cc1Br)OCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(OCC2CC2)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
1M Aqueous sodium hydroxide solution (30 mL) was added to a solution of cyclopropylmethyl [2-bromo-4-(cyclopropylmethoxy)phenyl]acetate (6 g) in methanol (50 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, water was added thereto, and the mixture was washed with diisopropyl ether. The aqueous layer was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.48 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[S:12][C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]3[C:21]=2[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCN(CC)CC.CC(=O)OCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]([NH:22][C:21]1[N:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:11]1[S:12][C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:9][CH:10]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2cnccn12
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
21.4 ml (155 mmol) of trimethylsilylacetylene, 2.4 g (12.9 mmol) of copper(I) iodide and 4.5 g (6.5 mmol) of bis(triphenylphosphine)-palladium(II) chloride were added to a solution of 45.3 g (129 mmol) of [2-(5-bromo-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-tert-butyl-amine (synthesis described in Example 18, part a) in DMF (760 ml) and NEt3 (90 ml). The reaction solution was heated to 60° C. for 4 h and stirred at RT for 16 h. The mixture was then combined with a 1M aq. Na2CO3 solution and diluted with EA. The phases were separated and the aq. phase was extracted with EA. The combined organic phases were washed with water and dried over MgSO4. After filtration and removal of the solvents under a vacuum, the resultant group was redissolved with an EA/DCM (1:1) mixture and filtered through diatomaceous earth. The filtrate was evaporated under a vacuum. 30.8 g (84 mmol, 65%) of tert-butyl-[2-(5-trimethylsilanylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained from the group were by crystallisation from tert.-butyl-methyl ether.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=[CH2:28].C(N(C(C)C)C(C)C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1/[CH:27]=[CH:28]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1scnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncsc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol), 4-methyl-5-vinylthiazole (44 mg, 0.35 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(o-MeC6H4)3 (16 mg, 0.052 mmol) in anhydrous MeCN (2 mL) were heated with stirring in a sealed tube under Ar at 90° C. for 1 d. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound (30 mg, 43%): 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 8.64 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.28 Hz, 1H), 7.83 (d, 1H), 7.64 (d, J=16.06 Hz, 1H), 7.12 (d, J16.31 Hz, 1H), 5.82 (s, 2H), 3.62 (t, J=8.28 Hz, 2H), 2.62 (s, 3H), 0.92 (t, J=8.28 Hz, 2H), −0.05 (s, 9H); MS ESI 400.2 [M+H]+, calcd for [C20H25N3O2SSi+H]+ 400.6.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:33]1[NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:45](=[O:46])[NH:44][CH2:43][CH2:42][C:41]=1[C:40]=23.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]1[NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:45](=[O:46])[NH:44][CH2:43][CH2:42][C:41]=1[C:40]=23
Reactant: Oc1ccccc1I
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: O=C1NCCc2c(-c3ccccc3O)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Example YY, 2-iodophenol (220 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino)ferrocenedichloro palladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 2-(2-hydroxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 40 mg (15%) as a white solid: m.p. 305° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.86 (m, 2H), 3.46 (m, 2H), 6.92 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.24 (m, 1H), 7.34 (dd, J=7.5, 1.2 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 8.00 (br t, 1H), 9.84 (br s, 1H), 11.20 (br s, 1H). MS (FAB, MH+): 279. Anal. (C17H14N2O2.0.44 CHCl3) C, H, CHCl3) C, H, N.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[C:6]([CH3:22])=[N:5]1)([CH3:3])[CH3:2].O[Li].O>>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[C:6]([CH3:22])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cn[nH]c2)cc2c1c(C)nn2C(C)C
Agent: [Li]O
Solvent: O
Product: Cc1nn(C(C)C)c2cc(-c3cn[nH]c3)cc(C(=O)O)c12

Procedure:
The title compound was prepared from methyl 1-isopropyl-3-methyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylate (0.2 g, 0.67 mmol) and LiOH.H2O (0.084 g, 2.01 mmol) in the same manner as described for example 80 (step b). The product was collected as a white solid (0.2 g). 1H NMR (DMSO-d6, 400 MHz): δ 1.467 (d, J=6.4 Hz, 6H), 2.568 (s, 3H), 4.984-5.048 (m, 1H), 7.790 (s, 1H), 8.058 (s, 1H), 8.219 (brs, 2H), 13.05 (brs, 2H). LCMS (ES+) m/z: 285.10 [M+H].
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33]>O1CCOCC1>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:32](=[O:33])[O:31][CH3:30])[S:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The compound of Example 362 (0.622 g; 2.0 mmol) is dissolved in dioxane (100 ml) cooled down to 0° C. Triethylamine is added, then, dropwise, methylchloroformate (2.5 mmol). The reaction medium is then stirred for 3 hours at ambient temperature before being poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is purified on a silica column (eluent: 10% acetone in dichloromethane). The pure fractions are combined and the solvents are evaporated off in order to produce an off-white solid with a yield of 46.0%. Melting point: 151-153° C.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]([C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1)=[O:18].[C:25]([C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([CH:37]=1)[C:34](O)=[O:35])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[C:23]([NH:24][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([C:25]([CH3:26])([CH3:27])[CH3:28])[CH:30]=[CH:31][C:32]=2[O:38][CH3:39])=[CH:22][NH:21][N:20]=1)=[O:18]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Reactant: COC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]cc1NC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of EDC (11.59 g, 60.7 mmol), HOBt (8.19 g, 60.7 mmol) and 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (7.84 g, 55.6 mmol) in DMF (100 ml) was added 5-tert-butyl-2-methoxy-benzoic acid (10.52 g, 50.6 mmol) and the mixture stirred at room temperature overnight. The mixture was reduced in vacuo and the residue partitioned between EtOAc (500 ml) and brine (200 ml), the organic portion was washed with saturated aqueous sodium hydrogen carbonate (200 ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester as a pale yellow solid (17.07 g, 93%). (LC/MS (acidic method): Rt 3.12 min, [M+H]+ 332).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH3:29])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]4[CH2:28][CH3:29])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: CC[C@H]1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 112 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The enantiomers of this product were separated by chiral HPLC, with compound 195 coming from the first peak to elute. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 439. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.74 (s, 1H), 8.38 (d, 2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.00 (d, 2H), 6.74 (s, 1H), 4.58 (m, 6H), 4.07 (m, 4H), 3.25 (m, 3H), 3.07 (t, 2H), 1.39 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([CH:15]=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[OH:18]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C1COCC1.O.C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:18])=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (10.0 g, 29.2 mmol) and sodium phosphate monobasic (10.1 g, 73 mmol, Aldrich) were stirred vigorously in 35 mL each of THF, tert-butanol, and water at 0° C. 2-Methyl-2-butene (45.2 mL, 2.0 M in THF, Aldrich) was added to the reaction mixture, followed by sodium chlorite (6.06 g, 67.1 mmol, Aldrich). The ice bath was removed and the reaction mixture was warmed to room temperature, stirring very rapidly. After a few minutes the desired product began precipitating out of solution. Stirring was continued for 1 h, then 20 mL of 1N aqueous HCl was added, and stirring was continued for another 5 minutes. The desired product was filtered off, then washed with water, ethyl acetate, and ether. The filtrate was taken and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in ethyl acetate, filtered, and washed with ethyl acetate and ether to yield additional desired product. The pale yellow solids were combined to yield 8.22 g (78%) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (92% pure, 8% starting material remaining). This material was dissolved in a minimal amount of 1N aqueous NaOH. Ethyl acetate was added and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified, with stirring, using concentrated HCl to pH 1. The pale yellow solid that precipitated out of solution was collected, washed with water, ethyl acetate, diethyl ether and then dried under vacuum to afford 7.33 g (70%) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (95.4% pure by HPLC). 1H NMR (DMSO-d6) δ 13.53 (s, 1H), 7.52-7.49 (m, 3H), 7.38 (t, 2H, J=8.8 Hz), 6.81 (d, 1H, J=7.2 Hz); MS(ESI+) m/z 360.14 (M+H)+.