Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([CH2:5][NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[NH:1][CH:22]=[O:24]
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
0.90 g (2.82 mmol) of the 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline prepared in Example 151 was dissolved in 15 ml of formic acid, followed by the addition of 1 ml of acetic anhydride. The obtained mixture was stirred at room temperature for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 0.64 g of the title compound as a pale yellow crystal.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[OH-].[K+].Cl>O>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCc2ccccc2)cc1

Procedure:
A mixture of 6.0 g. of ethyl p-benzylaminobenzoate (prepared as described in Example 9), 100 ml. of ethanol-water (9:1) and 6.0 g. of potassium hydroxide are refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water, chilled, filtered and the solid washed with water to give pale cream crystals, m.p. 165°-168° C. Recrystallization from ethanol gives tan crystals, m.p. 167°-169° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19](=[S:21])[NH:20][C:16]=2[CH:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([N:18]2[C:17]3[CH:28]=[CH:29][C:14]([Cl:13])=[CH:15][C:16]=3[NH:20][C:19]2=[S:21])[CH2:27][CH2:26]1
Reactant: S=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: BrCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: S=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2COc3ccccc3O2)CC1

Procedure:
2.3 g of 2-bromomethyl-1,4-benzodioxane, 2.35 g of 4-(5-chlorobenzimidazole-2-thion-1-yl)-piperidine, 1.4 ml of triethylamine and 0.3 g of sodium iodide were warmed at 60° C. in 25 ml of anhydrous dimethylformamide for 60 hours, and the mixture was then poured onto ice-water. The precipitate which had separated out was filtered off with suction, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:31])[OH:30].Br.[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.[OH-].[K+]>CN1CCCC1=O.C1(C)C=CC=CC=1>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:13]3[O:16][C@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:31])[OH:30])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Clc1nc[nH]c2nccc1-2
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C[C@]1(O)[C@H](n2ccc3c(Cl)ncnc32)O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To the compound from Step C (0.70 g, 1.3 mmol) was added HBr (5.7 M in acetic acid, 2 mL). The resulting solution was stirred at room temperature for 1 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×10 mL). 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (0.5 g, 3.3 mmol) and powdered KOH (85%, 150 mg, 2.3 mmol) were stirred in 1-methyl-2-pyrrolidinone (5 mL) for 30 min and the mixture was co-evaporated with toluene (10 mL). The resulting solution was poured into the above bromo sugar residue and the mixture was stirred overnight. The mixture was diluted with toluene (50 mL), washed with water (3×50 mL) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with (EtOAc/Hexane 15/85) to afford a solid (270 mg).
Reaction SMILES: [CH2:1]1[C:20]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:19]=2)[CH2:3][CH2:2]1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[CH2:1]1[C:20]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]5[NH:23][N:22]=[N:21][N:18]=5)[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:19]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)Sc1cc3c(cc1C=C2)CCC3
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=Cc2cc3c(cc2Sc2cc(-c4nnn[nH]4)ccc21)CCC3
Yield: 64.1 %

Procedure:
A solution of 2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carbonitrile (2.10 g, 7.625 mmole) in dimethylformamide (31.5 ml) stirred under reflux (oil-bath at 170°-180° C.) in an atmosphere of argon was treated with a mixture of sodium azide (743 mg, 11.44 mmole) and ammonium chloride (612 mg, 11.44 mmole). An equal portion of sodium azide and ammonium chloride was added after 1 hour and then at 30 minute intervals seven portions of a mixture of sodium azide (247 mg, 3.81 mmole) and ammonium chloride (204 mg, 391 mmole) were added. After heating for a further 1 hour the reaction mixture was allowed to cool, then it was diluted with water (150 ml) and acidified. An extraction with methylene chloride (250 ml) was performed. The methylene chloride solution was extracted with a mixture of water (100 ml) and 5N sodium hydroxide (10 ml) and after a further wash with water the combined aqueous extract on acidification yields 1.555 g of title compound.
Reaction SMILES: [NH3:1].[CH3:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4]>O1CCCC1>[CH3:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(N)(=O)=O)cc1

Procedure:
To concentrated aqueous ammonia (1.75 mL) in tetrahydrofuran (50 mL) at 0° C. with stirring was added over 2 min via syringe 4-(1-methylethyl)benzenesulfonyl chloride (3.3 g). A white precipitate was observed. Additional concentrated aqueous ammonia (1.75 mL) was added after 5 min. After 4 h volatiles were evaporated and the residue partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and volatiles evaporated to give the title crude compound as a colourless powder that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=O)[N:6]([CH3:8])[CH:7]=1)#[N:2].[NH2:11]CC1N(C)C(C#N)=CC=1>>[NH2:11][CH2:9][C:5]1[N:6]([CH3:8])[CH:7]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: Cn1cc(C#N)cc1C=O
Reactant: Cn1c(C#N)ccc1CN
Product: Cn1cc(C#N)cc1CN

Procedure:
5-Aminomethyl-1-methylpyrrole-3-carbonitrile were prepared starting from 4-cyano-1-methylpyrrole-2-carbaldehyde similar to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N:25]1C=CC=C(CN)[CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:26]=[N:25][CH:22]=[CH:23][CH:24]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2cccnc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using 1-pyridin-3-ylmethanamine instead of (pyridin-2-ylmethyl)amine to afford the crude product. The solvent was removed by distillation, and the crude product was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford the titled compound as the trifluoroacetate as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.34 (m, 5H), 1.50-1.61 (m, 3H) 1.62-1.69 (m, 2H), 1.87 (s, 3H), 2.23 (s, 3H), 3.71-3.79 (m, 1H), 4.63 (d, J=5.10 Hz, 2H), 7.60 (d, J=7.79 Hz, 1H), 7.64 (dd, J=7.66, 5.24 Hz, 1H), 8.05 (d, J=7.79 Hz, 1H), 8.62 (d, J=4.57 Hz, 1H) 8.62-8.69 (m, 1H) 8.71 (s, 1H), 12.61 (bs, 1H); MS (ESI) m/z 312.5 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (17 mg, 0.057 mmol), N3-(3-Fluoro-phenyl)-1H-indazole-3,5-diamine (14 mg, 0.057 mmol) and PyBroP (27 mg, 0.057 mmol) in methylene chloride (1 ml) was added diisopropylethylamine 20 μL. The mixture was allowed to stir overnight at room temperature and the titled compound (7.5 mg, 25%) was purified with HPLC. MS (ESI) m/z=493 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ8.02 (s, 1H), 7.38-7.30(m, 3H), 7.23-7.15 (m, 2H), 7.01-6.99 (m, 2H), 6.91-6.86 (m, 2H), 6.58-6.53 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22](C(C1C2C(=CC(OC)=CC=2)C(OC)=CC=1)=S)[CH3:23]>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22]([C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])[CH3:23]
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Reactant: COC(=O)CN(C)C(=S)c1ccc(OC)c2cc(OC)ccc12
Product: COC(=O)CN(C)C(=O)c1ccc(OC)c2cc(OC)ccc12

Procedure:
By following serially the procedures of examples 2 and 3 and using an equivalent amount of 4,6-dimethoxy-1-naphthalenecarboxylic acid of example 61 instead of 5-bromo-1-naphthalenecarboxylic acid; N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (I, R1 and R2 =CH3, R3 =4-CH3O, R4 =6-CH3O and R5 =H); mp 105°-107° C.; NMR(CDCl3) δ3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0 (s, 3H), 4.8 (2d, J=20 Hz, 2H), 7.3 (m, 5H); was obtained via N-[(4,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester; NMR(CDCl3) δ2.75 (s, 3H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 7.4 (m, 5H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17]OC(=O)C(C)(C)C)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.Cl.C(N1CCNCC1)(C)C.O[N:37]1[C:41]2C=[CH:43][CH:44]=[CH:45][C:40]=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17][N:37]3[CH2:43][CH2:44][CH2:45][CH2:40][CH2:41]3)[S:15][CH:16]=2)=[O:11])[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)N1CCN(C(=O)c2csc(COC(=O)C(C)(C)C)n2)CC1
Agent: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)N1CCN(C(=O)c2csc(CN3CCCCC3)n2)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
2,2-Dimethyl-Propionic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. The crude product from Step A (6.42 g, 24.2 mmol), 1-isopropyl-piperazine dihydrochloride (5.36 g., 26.68 mmol) and 1-hydroxybenzotriazole (4.915 g., 36.38 mmol) were dissolved into a mixture of N-methylmorpholine (14.72 g., 101.20 mmol) and DCM (120 mL). The mixture was stirred for 30 min under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.97 g, 36.4 mmol) was added, and the reaction mixture was stirred for 18 h at rt. The reaction was quenched by the addition of 1 M NaOH (25 mL), and was stirred for 1 h. The mixture was diluted with water and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to yield dark brown crude oil (6.2 g). The crude product was purified on silica gel column using 30-50% acetone-DCM to give the title compound as a brown oil (3.9 g, 46%). 1H NMR (500 MHz, CDCl3): 7.89 (s, 1H), 5.38 (s, 2H), 3.90-3.84 (m, 2H), 3.81-3.75 (m, 2H), 2.75-2.69 (m, 1H), 2.62-2.50 (m, 4H), 1.27-1.23 (s, 9H), 1.05 (d, J=6.3, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[O:65]([CH2:69][CH2:70]O)[CH2:66][CH2:67][OH:68]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:70][CH2:69][O:65][CH2:66][CH2:67][OH:68])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)OCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150 mg, 0.243 mmol) in methylene chloride (8 mL) was added triethylamine (72.0 mg, 0.10 mL, 0.717 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 92 mg, 0.365 mmol). The mixture was stirred at room temperature for 10 min before 2,2′-oxydiethanol (Aldrich, 154 mg, 0.14 mL, 1.45 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-(2-hydroxyethoxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (40.8 mg, 23% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6 [(M+H)+]: 704. found: 704.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([O:20][CH2:21][CH2:22][OH:23])([CH2:5]3)[CH2:3]1)[CH2:9]2.[I:24]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]12[CH2:3][C:4]3([O:20][CH2:21][CH2:22][OH:23])[CH2:10][C:8]([CH3:11])([CH2:7][C:6]([CH2:13][N:14]4[C:18]([CH3:19])=[C:17]([I:24])[CH:16]=[N:15]4)([CH2:5]3)[CH2:12]1)[CH2:9]2
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the 2-({3,5-dimethyl-7-[(5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.13,7]dec-1-yl}oxy)ethanol (3.5 g, 11 mmol) in N,N-dimethylformamide (30 ml) was added N-iodosuccinimide (3.2 g, 14.22 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with ethyl acetate and washed with aqueous sodium thiosulfate, water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36](=O)[O:37]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C.CCOC(C)=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)NCC3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of ethyl 2-(indolin-6-yl)thiazole-4-carboxylate (28D) (56 mg, 0.14 mmol), K2CO3 (22 mg, 0.16 mmol), and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (48 mg, 0.15 mmol) was heated to reflux in acetonitrile (3 mL) for 5.5 hours. The reaction mixture was cooled to rt and diluted in EtOAc (5 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc (1:1), to provide 22 mg (34%) of the desired product ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E): 1H NMR (300 MHz, CDCl3) δ 8.67 (1H, s), 8.12 (1H, s), 7.68 (2H, m), 7.52 (1H, m), 7.38 (1H, m), 7.25 (2H, m), 4.43 (2H, q), 4.22 (2H, m), 3.18 (2H, m) 1.45 (3H, t). LC/MS (APCI): m/z 451.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].Cl.[OH-].[Na+]>O.C(O)C>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2c(C)cccc2C)nc(-c2ccccn2)n1
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol), 2,6-dimethylaniline (45 μl, 0.365 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (75 ml), which was washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow oil (58 mg, 82%). 1H NMR (CDCl3): 8.81-8.78 (m, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.83-7.77 (m, 1H), 7.36-7.30 (m, 1H), 7.21-7.13 (m, 3H), 6.91 (s, 1H), 5.77 (s, 1H), 2.39 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: [CH:1]1([C:13](O)=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[CH3:16][O:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:20][C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH:1]1([CH2:13][N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([O:17][CH3:16])=[CH:26][C:22]4[CH2:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:32][CH2:31]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: O=C(O)C1Cc2cccc3cccc1c23
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3Cc4cccc5cccc3c45)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from acenaphthen-1-ylcarboxylic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 226°-228° C. (ethanol).
Reaction SMILES: CN1C=NN=C1S(CC1C=CC(C(O)=O)=CC=1)=O.[CH3:19][N:20]1[CH:24]=[N:23][N:22]=[C:21]1[S:25]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=1)(=[O:27])=[O:26].[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:33](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([CH2:28][S:25]([C:21]3[N:20]([CH3:19])[CH:24]=[N:23][N:22]=3)(=[O:26])=[O:27])=[CH:37][CH:36]=2)=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Agent: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzamide.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C1COCC1.[Cl-].[Na+].O>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl acetoacetate (3.98 mL) in THF (dry) (50 mL) was added NaH (1.571 g) at 0° C., and the mixture was stirred for 30 min at the same temperature. To the mixture was added 3-bromo-1,1,1-trifluoroacetone (5 g) 0° C., and the mixture was stirred for 3 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.570 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Yield: 136.1 %

Procedure:
A mixture of Toluene-4-sulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (4.47 g; 13.9 mmol; 1.0 eq.), 4-Iodo-1H-pyrazole (2.69 g; 13.9 mmol; 1.0 eq.) and cesium carbonate (6.78 g; 20.8 mmol; 1.5 eq.) was heated in DMA (50.0 mL) at 100° C. for 3 h. It was then allowed to cool to RT, diluted with EtOAc and washed with water and brine. Aqueous phases were back-extracted with EtOAc. Combined organic phases were finally dried over sodium sulfate, filtered and concentrated to give 6.32 g of a yellow oil. Recrystallisation in iPrOH afforded the title compound as a white powder (2.81 g, 61%). HPLC (Condition A): Rt 3.46 min (purity 100%). MS (ESI+): 335.1.