Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:44]([O:43][C:42](=[O:51])[NH:41][CH2:40][CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:17][CH:16]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCOc1ccc(-c2nc(-c3ccccc3)cs2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
4-(4-Phenyl-thiazol-2-yl)-phenol (516 mg, 2.03 mmol) was dissolved in toluene (6.8 ml), and triphenylphosphine (786 mg, 3.00 mmol) and benzyl N-(2-hydroxyethyl)-carbamate (585 mg, 3.00 mmol) were added. The solution was cooled to about 0° C. and 1,1-(azodicarbonyl)-dipiperidine (757 mg, 3.00 mmol) was added. The mixture was allowed to stir for about 10 minutes at about 0° C. and was then allowed to warm to room temperature. An additional 6.8 ml of toluene and 6.8 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and then the solids were filtered off and rinsed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to a semisolid which was then purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride) to give 396 mg of pure product (45% yield). LRMS ([M+H]+)=430.9.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(OC(C)(C)C)=O.C(C1C=CC=CC=1B(O)O)=O.[BH4-].[Na+].N1CCCC1>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1B(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: c1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A mixture of N-BOC-indole (2.0 g, 6.7 mmol) and 2-formyl benzene boronic acid (1 g, 6.7 mmol) was diluted with THF (20 mL) and 2M sodium carbonate (10 mL), then deoxygenated by a rapid stream of nitrogen applied to the system for 20 min, followed by treatment with Pd(0). The reaction was refluxed for 18 h, cooled down, filtered through Celite® and washed with THF (20 mL). The filtrate evaporated to dryness, taken up in water, and extracted with EtOAc (3×). The EtOAc extracts were dried over sodium sulfate and concentrated. The crude residue (1 g, 1.5 mmol) was treated with sodium borohydride (0.14 g, 1.5 mmol) and pyrrolidine (0.3 mL, 1.5 mmol). The reaction mixture was stirred for 18 h, diluted with ice water and extracted with EtOAc. Ethyl acetate extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford an intermediate indole (0.27 g), that was treated with TFA (10 mL) and sodium cyanoborohydride (43 mg, 0.7 mmol). The reaction mixture was stirred for 4 h, concentrated and purified through a plug of silica gel (hexane/EtOAc, 1:1) to afford the desired product (0.25 g, 29% over last 2 steps). LRMS (ES+): 279.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH3:21][Sn](C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C=O)ccc1C
Yield: 82.9 %

Procedure:
A mixture of methyl 5-formyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (4.88 g), tetramethyltin (10.8 g), tetrakis(triphenylphosphine)palladium (1.85 g) and toluene (150 mL) was heated under reflux for 20 hrs. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give methyl 5-formyl-2-methylbenzoate as colorless crystals (2.31 g, yield 83%) from a fraction eluted with ethyl acetate-hexane (1:8, v/v). Recrystallization from diethyl ether-hexane gave colorless prism crystals. melting point: 60-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([NH:18][NH2:19])=[O:17].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:19][NH:18][C:16](=[O:17])[C:15]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:13]([OH:12])[CH:14]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)NN)cc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)Cc2ccc(Cl)cc2)cc1O
Temperature: 85 °C

Procedure:
A mixture of 4-chlorophenylacetyl chloride (1.36 g, 7.22 mmol) (Aldrich), 3-hydroxy-4-methyl-benzoic acid hydrazide (1.0 g, 6.02 mmol) (from Example 6 supra) and triethylamine (1.36 mL) in tetrahydrofuran (20 mL) was heated at 85° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue washed with ethyl acetate and dichloromethane and dried to give 3-hydroxy-4-methyl-benzoic acid N′-[2-(4-chloro-phenyl)-acetyl]-hydrazide. (Yield 0.91 g, 95%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:15][C:10]=1[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1 L) using 10% ethyl acetate-hexanes (˜4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=2.4 Hz, 1H), 7.29 (dd, J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:12])[CH2:10]Br.Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[S:23][CH:24]=[C:25]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[N:26]=2)[CH2:17][CH2:16]1.O>CN(C)C=O>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([C:25]2[N:26]=[C:22]([NH:21][CH:18]3[CH2:19][CH2:20][N:15]([CH2:10][C:9]([O:8][CH3:7])=[O:12])[CH2:16][CH2:17]3)[S:23][CH:24]=2)=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(-c2csc(NC3CCNCC3)n2)cc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(Nc2nc(-c3ccc(C#N)cc3)cs2)CC1
Temperature: 50 °C
Yield: 86 %

Procedure:
17.75 g of potassium carbonate and 4.3 ml of methylbromoacetate are added to 14.8 g of 4-{2-[(piperid-4-yl) amino]-1,3-thiazol-4-yl}benzonitrile dihydrochloride in 150 ml of N,N-dimethylformamide and the reaction mixture is heated at 50° C. for 2 hours. It is poured over water, extracted with ethyl acetate and the organic phase is washed with water, and then dried over sodium sulphate and concentrated under vacuum. The residue crystallizes from isopropyl ether to give beige crystals which melt at 172° C.; yield 86%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]/[N:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:17]N1C(=O)CCC1=O>C(OCC)(=O)C>[Cl:17]/[C:7](=[N:6]\[NH:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[F:1])/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C=N/NCc1ccccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Ethyl (2E)-[(2-fluorobenzyl)hydrazono]acetate (300 mg, 1.14 mmol) from example 1A are dissolved in ethyl acetate (2.0 ml). N-Chlorosuccinimide (143 mg, 1.07 mmol) is added, and the mixture is stirred at 60° C. for 1 h. It is then concentrated in vacuo, and the residue is stirred with carbon tetrachloride. The filtrate after filtration is concentrated. 292 mg (82% of theory) of the desired compound are obtained.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][N:13]([CH3:14])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CNCc1cccc2c1OCCCO2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1cccc2c1OCCCO2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 78.9 %

Procedure:
According to the procedure of Example 35g (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (239 mg, 1.24 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (318 mg, 1.25 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (385 mg, 79%) as a yellow solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.66-10.63 (m, 1H), 8.36-8.32 (m, 1H), 8.07-8.03 (m, 1H), 7.51-7.46 (m, 1H), 7.30-721 (m, 1H), 6.93-6.88 (m, 2H), 6.78-6.76 (m, 1H), 4.76-4.59 (m, 2H), 4.13-4.06 (m, 4H), 3.11-2.84 (m, 5H), 2.54-2.52 (m, 2H), 2.11-2.07 (m, 2H); ESI MS m/e 394 [C22H23N3O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([CH3:21])([OH:20])[CH3:19])[N:11]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>ClC(Cl)C.C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[N:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([OH:20])([CH3:21])[CH3:19])[N:11]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(Nc2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N(C(=O)Nc2ccccc2Cl)c2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-3-[4-(4-methoxy-phenylamino)pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 2, (129 mg, 0.427 mmol) in dichloroethane (3 mL) is added 2-chlorophenyl isocyanate (57 μL, 0.469 mmol) dropwise via syringe. The reaction is stirred at room temperature for 2 hours. Additional 2-chloroisocyanate (57 μL, 0.469 mmol) is added and the reaction mixture stirred at room temperature for 16 hours after which the reaction mixture is diluted with CH2Cl2 (30 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer is extracted with CH2Cl2 (20 mL) and the combined organic layers washed with water and brine and dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue which is purified over silica (5% to 20% Et2O/CH2Cl2 to 10% MeOH/CH2Cl2) to afford the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 13.04 (br s, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.37-7.16 (m, 4H), 7.17 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H), 5.56 (m, 2H), 4.05 (m, 1H), 3.85 (s, 3H), 1.30 (s, 3H), 1.25 (d, J=6.9 Hz, 3H), 1.23 (s, 3H); MS (ESI) m/z 456 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([O:30][C:31]1[C:40]2[C:35](=[CH:36][C:37](F)=[C:38]([Cl:41])[CH:39]=2)[CH:34]=[CH:33][N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(N(C)C)=O>[CH2:23]([O:30][C:31]1[C:40]2[C:35](=[CH:36][C:37]([O:14][C:11]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[C:38]([Cl:41])[CH:39]=2)[CH:34]=[CH:33][N:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1cc2c(OCc3ccccc3)nccc2cc1OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 86.2 %

Procedure:
566 mg of 1-Benzyl-4-phenyl-piperidin-4-ol (67) were dissolved in 6 ml of dry dimethyl acetamide. 48 mg of sodium hydride (95%) were added and after 1 h of stirring, 580 mg of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (61), dissolved in 6 ml of dry dimethyl acetamide were added. The course of the reaction was monitored by LCMS and 50 mg of sodium hydride were added several times until no further conversion could be observed. 10 mL of water were added. The resulting precipitate was purified by silica gel chromatography to give 930 mg of the desired product, sufficiently pure for further conversion. Rt=1.62 min (Method C). Detected mass: 536.2 (M+H+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH:35]=1)(=O)=O.C(OC(C1C(C2CCC(C(F)(F)F)CC=2)=C(C)SC=1C)C([O-])=O)(C)(C)C>>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(OC1=CCC(C(F)(F)F)CC1)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cc1sc(C)c(C(OC(C)(C)C)C(=O)[O-])c1C1=CCC(C(F)(F)F)CC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCC(C(F)(F)F)CC1

Procedure:
Using the procedure described in example 29, step 2, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (60 mg, 0,148 mmol) is converted, by reaction with 4-(trifluoromethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (41a) and after purification by preparative TLC (cyclohexane/ethyl acetate 90/10), to 2-(tert-butoxy)-2-{2,5-dimethyl-4-[4-(trifluoromethyl)cyclohex-1-en-1-yl]thiophen-3-yl}acetate (41b) (31 mg, 0.07 mmol, 50%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH3:9])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(I)ccn1
Yield: 95.4 %

Procedure:
500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91%) of crude 4-iodo-2-methoxypyridine.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([O:33][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:51]([OH:53])=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:47]([Si:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:33][C@H:31]1[CH2:32][N:28]([C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:27])[C@@H:29]([C:51](=[O:53])[N:16]([O:15][CH3:14])[CH3:17])[CH2:30]1)([CH3:48])([CH3:49])[CH3:50]
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)[C@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.50 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 761 mg of O,N-dimethylhydroxylamine hydrochloride were added in order to a pyridine (30 ml) solution of 2.62 g of (2R,4R)-4-(tert-butyl-diphenyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester obtained in (step 1), and the reaction liquid was stirred overnight at room temperature. The solvent of the reaction liquid was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].C[Si](C)(C)[O:8][C:9]1[CH2:12][CH2:11][C:10]=1[O:13][Si](C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:2]([CH:4]1[C:10](=[O:13])[CH2:11][CH2:12][C:9]1=[O:8])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Reactant: CC(C)C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)C1C(=O)CCC1=O
Yield: 16.6 %

Procedure:
To a solution of TiCl4 (1.47 g, 7.77 mmol) and isobutyraldehyde (559 mg, 7.75 mmol) in DCM (16 ml) under N2 at −78° was added a solution of 1,2-bistrimethylsilyloxycyclobutene (1.97 g, 8.56 mmol) in DCM (16 ml) maintaining a temperature of less than −70°. After 30 min the reaction was poured into water, extracted into DCM, washed (H2O×2), dried (MgSO4) and the solution concentrated in vacuo to yield a clear oil. To this oil was added TFA (20 ml) and the solution heated at reflux for 24 h. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2; 50:50 EtOAc/hexane) to give the title compound as an off-white solid (180 mg, 17%). δ H (d6-DMSO) 2.61 (1H, sept, J 7.0 Hz), 2.29 (4H, s), 1.04 (6H, d, J 7.0 Hz). m/z (ESI, 70V) 141 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:17]>CO.[Pd]>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:17]
Reactant: CCCCC(=Cc1ccc(F)c(C)c1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzylidene)-hexanoic acid (0.850 g, 3.600 mmol) in 20 mL of MeOH, was added Pd—C (10 wt % on activated carbon, 0.170 g). After stirring at room temperature under H2 for 16 h, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. LC-MS: tR=9.3 min; m/z 239 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[CH:26]=[C:25]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(C)c1ccn2c(Br)cnc2n1
Product: CC(C)(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-tert-butylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: Found C, 77.17; H, 5.79; N, 15.78. C23H20N4.0.3(H2O) requires C, 77.21; H, 5.80; N, 15.66; δH (400 MHz, CDCl3) 1.44 (9H, s), 7.05 (1H, d, J 7), 7.48-7.76 (7H, m), 7.83 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.88 (1H, d, J 7); m/z (ES+) 353 (M++H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:19]([CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: CC(=O)S[C@@H]1CO[C@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1

Procedure:
The title compound is prepared by the procedure of Example 43 using 0.560 gof product from Example 60 in 2 ml of methylene chloride, 0.569 g of tetrabutylammonium azide in 2 ml of methylene chloride to give 0.321 g of the desired product.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:14])=[O:13].C(ON=O)(C)(C)C>CC(O)=O.C1COCC1>[CH3:27][O:26][C:21]1[C:20]2[C:25](=[C:16]3[C:17](=[CH:18][CH:19]=2)[C:2]2[C:3](=[CH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[S:12](=[O:14])(=[O:13])[NH:15]3)[N:24]=[CH:23][CH:22]=1
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)cccc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccnc2c3c(ccc12)-c1cc(C(F)(F)F)ccc1S(=O)(=O)N3
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A solution of 2-amino-N-(4-methoxy-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 196) (454 mg, 1.1 mmol) in AcOH/THF (1:1, 10 ml) was cooled to 0° C. and tert-butylnitrite (235 mg, 2.2 mmol) was added. The reaction was stirred at 0-5° C. for 2 h. The reaction was quenched water (5 ml) and the solvent partially evaporated. The residue was dissolved in EtOAc (150 ml), washed with sat. sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (1:0-99:1) gradient elution followed by recrystallisation from iPA/MeCN to give the title compound (45 mg, 11%).
Reaction SMILES: [Cl-].[K+:2].[Cl-].[Na+:4].[P:5]([O-:9])([O-:8])([O-:7])=[O:6]>>[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[K+:2].[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[Na+:4]
Reactant: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: O=P([O-])(O)O

Procedure:
The fine particles of potassium chloride or sodium chloride and the fine particles of phosphate or a buffering agent may be separately prepared. For example, when a concentrated aqueous solution of potassium chloride or sodium chloride is formed, an aqueous solution of potassium dihydrogen phosphate and sodium dihydrogen phosphate (4:6 in molar ratio) can be separately formed. Both solutions are preferably in a saturation state, which provides a greater amount of fine particles, i.e., a high efficiency. Note that the weighed phosphates must be completely dissolved in water, because the proportion of the dissolved phosphates significantly affects the pH value. The thus-prepared aqueous solutions are poured into an organic solvent such as ethanol, in the same manner as described above, respectively, and the precipitated fine particles are collected.