Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12](Cl)([CH3:14])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:23]([Li])[C:22]([CH3:25])=[C:21]([CH3:26])[C:20]=1[CH3:27].O1CCC[CH2:29]1>>[C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12]([CH3:14])([CH3:13])[C:22]2([CH3:25])[CH:23]=[C:19]([CH3:18])[C:20]([CH3:27])=[C:21]2[CH3:26])[CH:8]=[C:9]([CH2:11][CH3:29])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Product: CCc1cc(C(C)(C)C)c(OC)c([Si](C)(C)C2(C)C=C(C)C(C)=C2C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane (5.24 g) synthesized in the above (3) and tetrahydrofuran (50 ml), tetramethylcyclopentadienyl lithium (2.73 g) was added at −35° C. and the mixture was heated to room temperature over 2 hours, followed by stirring at room temperature for 10 hours.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]([CH:14]([OH:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[C:12]([CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26](Cl)(=[O:28])[CH3:27].C(Cl)Cl.[OH2:33]>N1C=CC=CC=1.CN(C1C=CC=CN=1)C>[C:26]([O:22][C:14]([OH:33])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[C:13]1[CH:23]=[CH:24][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:11][C:12]=1[CH3:25])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O
Reactant: Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(O)(c1cccc(C)c1)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-t-Butyldimethylsilyloxymethyl-2,3'-dimethylbenzhydrol (6 g, 16.8 millimol) was dissolved in pyridine (10 ml), and thereto was added dimethylaminopyridine (200 mg, 1,6 millimol), and the mixture was cooled with ice. To the mixture were added acetylchloride (1.54 g, 19.6 millimol) and methylene chloride (10 ml). The mixture was returned to room temperature, and stirred for 2 hours. After adding water, the mixture was extracted with ethyl acetate, the organic layer was washed with in turn dil. hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate. The solvent was distilled away to give the title compound (6.9 g, 16.6 millimol, 99%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:20][C:16]1([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:21][C:22]4[N:27]=[C:26]([O:28][CH:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)[CH:25]=[CH:24][N:23]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91176.5 %

Procedure:
To the product of Step 4 (20 mg, 0.034 mmol) in DCM (1 mL) was added TFA (133 μL, 1.722 mmol). The mixture was stirred at ambient temperature for 1 hr. LCMS indicated complete reaction. To the reaction was added saturated aqueous NaHCO3 to adjust pH>8 and the product was extracted with ethyl acetate. The combined organic layer was dried, filtered and solvent removed in vacuo to afford 15 mg (0.031 mol, 91%) of N-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)acetamide as pale yellow oil. MS ESI: [M+H]+ m/z 481.2. 1H NMR (600 MHz, CD3OD): δ 8.16 (m, 2H); 7.90 (s, 1H); 7.55 (s, 1H); 7.30 (s, 1H); 6.26 (d, J=5.4 Hz, 1H); 5.58 (m, 1H); 3.34 (m, 2H); 3.21 (m, 2H); 2.65 (m, 2H); 2.40 (m, 2H); 2.22 (m, al); 2.14 (s, 3H); 2.01 (m, 4H). rhSYK activity=+++
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:21]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]1>N1C=CC=CC=1>[C:1]([O:27][CH2:26][C@H:25]1[O:28][C@@H:21]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:22][C@@H:23]1[OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 110 °C

Procedure:
In a 250-ml three-necked flask, trityl chloride is placed in anhydrous pyridine under inert gas and stirring, and the thymidine is added. After 30 minutes of heating to t=110° C. (heating-bath temperature), the yellowish reaction solution is allowed to cool and is then decanted slowly into 1.5 l of vigorously stirred ice water. After 30 minutes of stirring, the milky-white suspension is suction-filtered, the filter cake is dissolved in acetone and the solution is filtered once again. The solvent is removed in the rotary evaporator and the solid is dried for 16 hours in high vacuum. The product, 5′-O-tritylthymidine, is obtained by recrystallization two times from a benzene-acetone mixture.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.ClCCl>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: CC(C(N)=O)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)C(N)=O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a suspension of 2-(piperazin-1-yl)propanamide dihydrochloride (0.305 g, 1.33 mmol) in DMSO (1.5 mL), was added 1,1,3,3,-tetramethylguanidine (0.398 g, 3.45 mmol) at rt. The reaction mixture was stirred for 15 min. After that time 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.20 g, 0.664 mmol) was added as a solid in a single portion. The resulting mixture was stirred at 90° C. for 3.5 h. After that time the reaction was cooled to rt and diluted with dichloromethane (50 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 93:7 dichloromethane/methanol) to give 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide (0.080 g, 28%) as a light yellow solid: mp 149-150° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (br s, 1H), 7.65-7.79 (m, 2H), 7.30 (s, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.78 (s, 1H), 6.58 (s, 1H), 4.48 (br s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.64 (br s, 4H), 3.55 (br s, 2H), 2.54 (br s, 4H), 2.45 (t, 2H); ESI MS m/z 439 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(Cl)cncc1Br
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To the solution of 3-Bromo-5-chloro-pyridine-4-carbaldehyde (270 mg, 1.23 mmol) in THF (5 mL) and water (1 mL) was added NaBH4 (139 mg, 3.67 mmol). The resulting mixture was stirred for another 1 h, and was diluted with DCM. The organic layer was washed with water and brine. The aqueous layer was extracted with DCM. The combined extracts were separated and concentrated in vacuo to give 270 mg of title compound without further purification. ESI-MS m/z: 223.9 [M+1]+, Retention time 1.01 min. 1H-NMR (CDCl3, 400 MHz) δ 4.88 (s, 2H), 8.46 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[C:13]([OH:16])(=O)[CH3:14].Cl[C:18]1[C:19](=O)[C:20]([C:28]#N)=[C:21]([C:26]#N)[C:22](=O)[C:23]=1Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[O:16]=[C:13]1[C:14]2[CH:28]=[CH:20][C:19]3[NH:2][C:4]4[C:12]([C:18]=3[C:23]=2[CH2:22][CH2:21][CH2:26]1)=[CH:11][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: NNc1ccccc1C(=O)O
Reactant: CC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc1[nH]c3c(C(=O)O)cccc3c21
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
5.4 g (28.6 mmol) of 2-hydrazinobenzoic acid hydrochloride and 4.7 g (34.3 mmol) of zinc chloride were added to 300 ml of glacial acetic acid. Under stirring at about 85° C., 4.7 g (28.6 mmol) of the compound of Production Example 6 was added thereto over about 5 minutes. Then the obtained mixture was stirred at the same temperature for about 2 hours, brought back to room temperature and the precipitate was recovered by filtration. After concentrating the filtrate, water was added thereto and the precipitate thus formed was recovered by filtration. These precipitates were combined, dried and then dissolved in about 500 ml of dimethylformamide. Under stirring at room temperature, a solution of 6.5 g (28.6 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in tetrahydrofuran (20 ml) was added thereto and the obtained mixture was stirred for about 30 minutes. After concentrating, about 50 ml of ethanol was added and the precipitate thus formed was recovered by filtration to thereby give 3.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15](O)=[O:16])[CH:8]=[N:7]1.C(N(C(C)C)CC)(C)C.O.[OH:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=C[C:39]=2[N:38]=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1ON=C(CN)C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([NH:38][CH2:39][C:40]2[CH:41]=[C:42]([CH3:43])[O:35][N:36]=2)=[O:16])[CH:8]=[N:7]1
Reactant: O=C(O)c1ccnc(-n2cnn(Cc3ccc(F)c(F)c3)c2=O)c1
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(CN)no1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CNC(=O)c2ccnc(-n3cnn(Cc4ccc(F)c(F)c4)c3=O)c2)no1
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.1 %

Procedure:
A mixture of 2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinic acid (0.22 g, 0.66 mmol), diisopropylethylamine (0.6 mL, 9.57 mmol), 1-hydroxybenzotriazole monohydrate (0.20 g, 1.44 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.40 g, 1.24 mmol) and (5-methylisoxazol-3-yl)methanamine (0.19 g, 0.99 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 23 hours and concentrated in vacuo. The residue was suspended in a mixture of saturated sodium bicarbonate solution (10 mL) and ether (2.5 mL) and stirred at ambient temperature overnight. The solid was collected by filtration, washed with saturated sodium bicarbonate solution, water, ether, hexanes and dried in vacuo to afford 2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-((5-methylisoxazol-3-yl)methyl)-isonicotinamide as a colorless solid (0.20 g, 71% yield): mp 160-161° C.; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.46 (s, 1H), 7.70 (dd, J=5.1, 1.4 Hz, 1H), 7.25-7.09 (m, 4H), 6.03 (s, 1H), 4.96 (s, 2H), 4.67 (d, J=5.7 Hz, 2H), 2.41 (s, 3H); MS (ES+) m/z 427.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].ClCCC1C=C[C:38]([C:41](=[O:43])C)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:41]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1)(=[O:43])[CH3:38]
Reactant: CC(=O)c1ccc(CCCl)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)c1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-[4-(2-chloro-ethyl)-phenyl]-ethanone and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:9]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:11]=[CH:10][CH:8]2[NH:9][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(C=Cc2cccc(OC)c2)CCCC1
Product: COc1cccc(C=CC2CCCCC(=N)N2)c1
Product: Cl

Procedure:
The product of Example 164 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.ClCCl.[Cl:16][C:17]1[C:18]([CH:24]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)(=[O:27])=[O:26])=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>CN(C)C1C=CN=CC=1.CCCCCC>[Cl:16][C:17]1[C:18]([CH:24]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)(=[O:26])=[O:27])=[CH:19][C:20]([N:23]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[N:21][CH:22]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)(=O)N(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, methanesulfonyl chloride (0.034 ml, 0.44 mmol), triethylamine (0.062 ml, 0.44 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added to a dichloromethane (3 ml) solution of [5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]amine (63 mg, 0.15 mmol) at 0° C. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (73 mg, 0.12 mmol, 85%) as a white solid.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[N:21]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:7]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc2nc(N3CC[C@H](N4CCCC4)C3)sc2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of (R)-1-(6-bromobenzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 12, 0.50 g, 1.32 mmol), pyrrolidine (0.221 mL, 2.65 mmol), and potassium carbonate (0.549 g, 3.98 mmol) was placed in a 10 mL CEM microwave vial with a stirbar. N,N-Dimethylformamide (1.5 mL) was added, the vial was capped, and the reaction was heated to 100° C. under microwave irradiation for 15 minutes, then the cooling air was turned on and heating was continued at 70° C. for an additional 15 minutes. The reaction mixture was cooled to room temperature then partitioned between ethyl acetate and saturated aqueous sodium carbonate. The aqueous layer was extracted once more with ethyl acetate. The combined organic extracts were washed twice with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil that solidified on trituration with diethyl ether. The solid was collected by filtration and rinsed with diethyl ether, then purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF15-12g, 100% dichloromethane to 98:2 dichloromethane/methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was dried overnight in a vacuum oven at 70° C. to give (S)-2-(1,3′-bipyrrolidin-1′-yl)-6-bromobenzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.78-1.93 (m, 4H), 2.01-2.15 (m, 1H), 2.26-2.37 (m, 1H), 2.58-2.74 (m, 4H), 3.00-3.11 (m, 1H), 3.40-3.48 (m, 1H), 3.49-3.60 (m, 1H), 3.66-3.83 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.40 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[O:18]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:19])[N:1]1[CH:2]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(CC(=O)O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC(c1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
2.0 g of rac-3-amino-3-(4-fluorophenyl)propanoic acid (10.92 mmol) and 1.62 g of phthalic anhydride (10.92 mmol) were dissolved in 9 ml of DMF and heated at reflux at 135° C. overnight. The reaction solution was added to about 200 ml of water. The solid formed was stirred at RT for about 30 min and then filtered off, washed with water and dried under high vacuum. This gave 3.43 g of the title compound (86% of theory, purity about 86%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:22][C:19]([F:20])([F:21])[CH2:18][N:13]1[C:12]([C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(CC(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: FC(F)(F)Cn1nc2c(c1-c1ccc(C(F)(F)F)cc1)CCNCC2
Yield: 57.2 %

Procedure:
The title compound (128 mg) was prepared as in Example 177, Steps C and D, using 288 mg of 2-(2,2,2-trifluoro-ethyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 187, Step A) and 468 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C16H15F6N3, 363.12; found, m/z 364.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.93-7.83 (m, 2H), 7.62-7.54 (m, 2H), 4.75 (q, J=8.6 Hz, 2H), 3.47-3.39 (m, 2H), 3.38-3.27 (m, 2H), 3.24-3.15 (m, 2H), 2.87-2.76 (m, 2H).
Reaction SMILES: FC1C=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4]C=1.[F:11][C:12]([F:30])([F:29])[O:13][C:14]1[CH:15]=[C:16]([N:20]2[CH2:24][C@@H:23]3[C@@H:25]([NH2:28])[CH2:26][CH2:27][C@@H:22]3[CH2:21]2)[CH:17]=[CH:18][CH:19]=1.F[C:32](F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[C:5]([NH:8][C:9]([NH:28][C@@H:25]1[C@@H:23]2[C@@H:22]([CH2:21][N:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:12]([F:11])([F:29])[F:30])[CH:15]=3)[CH2:24]2)[CH2:27][CH2:26]1)=[O:10])([CH3:32])([CH3:6])[CH3:4]
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21
Product: CC(C)(C)NC(=O)N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 2-isocyanato-2-methylpropane for 1-fluoro-4-isocyanatobenzene and (3aR,4S,6aS)-2-(3-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 715 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 709: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.24 (d, J=8.2 Hz, 1H), 6.68 (dd, J=8.1, 0.9 Hz, 1H), 6.57-6.47 (m, 2H), 6.25 (d, J=7.1 Hz, 1H), 5.89 (s, 1H), 4.26-4.18 (m, 1H), 3.49 (dd, J=9.9, 3.2 Hz, 1H), 3.27 (dd, J=9.8, 7.8 Hz, 1H), 3.12 (dd, J=9.6, 7.8 Hz, 1H), 2.94 (dd, J=9.7, 3.4 Hz, 1H), 2.68-2.56 (m, 2H), 2.06 (td, J=12.6, 6.4 Hz, 1H), 1.85 (td, J=13.2, 7.7 Hz, 1H), 1.56-1.49 (m, 1H), 1.47 (s, 9H), 1.35-1.26 (m, 1H); MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:8])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[Cl:9][C:10]1[CH:21]=[C:20]([F:22])[C:19]([N:23]=[C:24]=[O:25])=[CH:18][C:11]=1[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]>>[NH2:5][C:4]1[N:23]([C:19]2[C:20]([F:22])=[CH:21][C:10]([Cl:9])=[C:11]([CH:18]=2)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:24](=[O:25])[N:1]=[C:2]([CH3:8])[C:3]=1[C:6]#[N:7]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CC(N)=C(C#N)C#N
Product: Cc1nc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(N)c1C#N

Procedure:
using 3-amino-2-cyanocrotononitrile and isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate there is obtained isopropyl 5-[6-amino-5-cyano-4-methyl-2-oxo-1(2H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 255°-257° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)cn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-iodo-pyrazol-1-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (0.67 g, 2.01 mmol) in DCM (25 ml), were sequentially added triethylamine (0.84 ml, 6.04 mmol) and benzenesulfonyl chloride (0.31 ml, 2.42 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc, and washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylsulfonamido)acetate (370 mg; 46% yield).