Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=O)[CH:11]=2)[CH2:6]1)=[O:4].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:19]1([CH2:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:18])([F:17])[F:1])[CH2:14][CH2:13]3)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N1CCc2cc(CN3CCC3)ccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbaldehyde (7.776 mmol, 1 equiv.) and azetidine (9.331 mmol, 1.2 equiv.) were dissolved in 1,2-dichloroethane (37 ml), and the mixture was stirred for 10 minutes at 25° C. Sodium triacetoxyborohydride (10.89 mmol, 1.4 equiv.) was added, and the reaction mixture was stirred for 16 hours at 25° C. Saturated sodium hydrogen carbonate solution (50 ml) was then added, the phases were separated, and the aqueous phase was extracted with dichloromethane (4×20 ml). The combined organic phases were washed with saturated NaCl solution (1×50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/dichloromethane/hexane/methanol/-ammonia (25% aq), 30:10:10:2:0.02). Yield: 1.55 g (67%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[OH:13])=[O:4].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[O:13][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:4]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(Nc1ccc(Cl)cc1O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2NC(=O)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a solution of 2-trifluoroacetylamino-5-chlorophenol (350 mg) and methyl 4-bromomethylbenzoate (435 mg) in DMF (3 ml), potassium carbonate (263 mg) was added at room temperature. The mixture was stirred for 1.5 hours at 60° C. After the termination of reaction, the reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (353 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1
Reactant: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) (0.34 g, 1.2 mmol) and 1-(5-aminopyridin-2-yl)-4-phenylpiperidine (B-6) (0.25 g, 1.0 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. then triethyl amine (0.16 mL, 1.2 mmol) was added. The reaction mixture was stirred for 2 h while the temperature was warmed slowly up to 0° C. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0-50% EtOAc/hexane gradient) to yield 1-(5-(2-bromo-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)-4-phenylpiperidine (A-40) (0.19 g, 35% yield) as a yellow solid. Note: the product A-40 contains compound with the bromine atom exchanged for a chlorine atom. 1H NMR (500 MHz, CDCl3) δ 9.58 (br s, 1H), 8.59 (br s, 1H), 8.34 (dd, 1H, J=9.5, 1.8 Hz), 7.35 (m, 2H), 7.30-7.22 (m, 3H), 6.89 (d, 1H, J=9.4 Hz), 4.42 (d, 2H, J=13.3 Hz), 3.17 (t, 2H, J=12.7 Hz), 2.85 (m, 1H), 2.05 (m, 2H), 1.84 (m, 2H); LCMS (ESI) calcd for [M+1]+ for chloride 451.1. found 451.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[OH:31][CH2:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:36]=[CH:35][CH:34]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cccc(CO)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 19 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (100 mg, 0.20 mmols), [3-(hydroxymethyl)phenyl]boronic acid (91 mg, 0.60 mmols), cesium carbonate (400 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (20 mg, 19%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[NH2:9])[N:3]=1.O=[C:12]1[CH2:18][CH:17]2[N:19]([C:20]([O:22][CH:23]([Cl:25])[CH3:24])=[O:21])[CH:14]([CH2:15][CH2:16]2)[CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([N:8]([CH3:10])[N:9]=[C:12]2[CH2:13][CH:14]3[N:19]([C:20]([O:22][CH:23]([Cl:25])[CH3:24])=[O:21])[CH:17]([CH2:16][CH2:15]3)[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CN(N)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cl)OC(=O)N1C2CCC1CC(=NN(C)c1cccc(Br)n1)C2
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (1.60 g, 7.90 mmol), 1-chloroethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 7.90 mmol) and p-toluenesulphonic acid (300 mg, 1.60 mmol) in toluene (50 mL) was heated under reflux, with water removal (azeotrope), for 3 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (676 mg, 28%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.68-6.65 (m, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.63-4.40 (m, 3H), 3.17 (s, 3H), 2.93-2.90 (m, 1H), 265-2.62 (m, 1H), 2.42-2.37 (dd, J=16.0, 6.0 Hz, 1H), 2.13-2.00 (m, 3H), 1.85 (d, J=6.0 Hz, 3H), 1.80-1.73 (m, 1H).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:8]([O:1][CH2:8][C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1)[C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Yield: 82 %

Procedure:
Compound 11a (Rb═H, 2.0 g, 6.34 mmol) was dissolved in DCM/water, 2/1, v/v (30 ml) and to this solution was added sodium hydroxide (2N, 10 ml). To this mixture was added tetrabutylammonium bromide (0.2 g, 0.63 mmol, 0.1 eq) and 4-chlorobenzyl bromide (1.43 g, 6.98 mmol, 1.1 eg). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis (100% DCM, Rf 0.55) showed complete reaction. The mixture was diluted with DCM (15 ml/mmol), the layers were separated and the water layer was extracted with DCM. The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/petroleum ether, 3/1 to 1/0, v/v) to give compound 12 (Ra=4Cl, Rb═H, 2.3 g, 82%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H); 2.75 (bs, 2H); 3.75 (bs, 2H); 4.35 (bs, 2H); 5.05 (s, 2H); 6.4 (s, 1H), 6.94 (d, 1H); 7.30-755 (m, 7H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:7]=4[C:8]=3[CH:9]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 2-(3-Fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.59 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 60% yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[CH3:27][C:28]([NH2:42])([CH3:41])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1.FC(F)(F)C([O-])=O>>[CH3:41][C:28]([NH:42][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:27])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=1
Reactant: CC(C)(N)Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(Cc1ccc(OC(F)(F)F)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The target compound is obtained by reacting 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one with 233 mg (1 mmol) 1,1-dimethyl-2-(4-trifluoromethoxy-phenyl)-ethylamine using the method described for Example 2c). Beige solid. Yield: 279 mg (50%, trifluoroacetate); mass spectroscopy: [M+H]+=441.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Li+].I[CH2:38][CH3:39]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([O:24][CH2:38][CH3:39])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCI
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (276 mg, 0.585 mmol) in NMP (3 mL) was added lithium hydroxide (28.0 mg, 1.170 mmol) and iodoethane (142 μL, 1.754 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-50% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak OJ-H, 21×250 mm, MeOH in CO2) to afford 4-(5-chloropyridin-3-yl)-2-((R)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-(S)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C29H30ClN5O [M+H]+ 500. found 500. 1H NMR (600 MHz, CD3OD) δ 8.75 (d, J=2.3, 1H), 8.70 (d, J=1.6, 1H), 8.27 (s, 1H), 8.23 (t, J=2.0, 1H), 7.49 (d, J=7.2, 2H), 7.38 (t, J=7.3, 2H), 7.36-7.31 (m, 1H), 5.94 (s, 1H), 4.01-3.85 (m, 2H), 3.68-3.59 (m, 2H), 1.44-1.36 (m, 2H), 1.27 (t, J=7.0, 3H), 1.07-0.98 (m, 1H), 0.89-0.78 (m, 1H), 0.76-0.66 (m, 5H), 0.64-0.54 (m, 1H), 0.54-0.46 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][CH:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=O.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([NH:22][C:15](=[O:17])[CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[S:6][C:2]=2[Br:1])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cc1nc(-c2ccc(Cl)cc2)sc1Br)Nc1ccccc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 5-bromo-2-(4-chlorophenyl)thiazol-4-yl-acetic acid (1 g, 3 mmol), thionyl chloride (2 equiv., 0.72 g, 6 mmol), and chloroform were heated under reflux for 2.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in CHCl3 (dry), followed by dropwise addition of aniline (2 equiv., 0.56 g, 6 mmol) and the resulting mixture refluxed for a further 5 hours. The reaction mixture cooled to room temperature and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc, and filtered to yield the desired product (0.4 g, 32%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]1([CH:15]([OH:32])[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:32]([CH:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=2)[CH2:22][CH2:23]1)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(NC2CCN(CCC(O)C3CCCCC3)CC2)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
After adding tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) to a solution of 1-(3-cyclohexyl-3-hydroxypropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (405 mg, 1.22 mmol), triethylamine (0.20 mL) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in methylene chloride (5 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. Triethylamine (0.20 mL), 4-dimethylaminopyridine (30 mg, 1.5 mmol) and tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) were further added to the reaction mixture and stirring was continued at room temperature for 70 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as a colorless oil (423 mg) (77.7% yield).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH2:6][CH:3]3[CH2:4][CH2:5][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 31.4 %

Procedure:
Using N-(pyrrolidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (168 mg, 0.500 mmol) and 3-(methoxycarbonyl)phenylboric acid (180 mg, 1.00 mmol), the same procedure was followed as in Example 2 to give 73.7 mg (31%) of the desired compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][N:13]=[C:14]=[S:15].BrBr>C(O)(=O)C>[CH3:12][NH:13][C:14]1[S:15][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:11])[C:2]=2[N:1]=1
Reactant: CN=C=S
Reactant: Cc1c(N)cccc1C(=O)O
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2c(C)c(C(=O)O)ccc2s1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
99 g of 3-amino-2-methylbenzoic acid (0.655 mol) were initially charged in 500 ml of acetic acid and, at 80° C,. admixed with 51 g of methyl isothiocyanate (7 mol) in 100 ml of acetic acid. After 2 h, 106 g of bromine (0.66 mol) in 20 ml of acetic acid were added dropwise at 50° C. The mixture was subsequently heated at about 100° C. for 2 h and, after the reaction had ended, allowed to cool. The precipitate was filtered off, the filtrate was concentrated to about 50 ml and the remaining filtrate and the precipitate were added to water. The aqueous phase was adjusted to pH 5 and the precipitate was filtered off at 8° C. It was subsequently washed with water and dried. Yield: 66 g (42%).