Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12])#[N:2].[I-].C[N+:15](C)(C)N.[O-]OOO[O-].[Na+].[Na+].Cl>CS(C)=O>[NH2:15][C:5]1[C:4]([OH:12])=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: C[N+](C)(C)N
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Reaction time: 8 h

Procedure:
Compound 477A (0.438 g, 2.67 mmol) was dissolved in 25 mL of DMSO and trimethylhydrazinium iodide (0.534 g, 2.67 mmol) was added. Sodium pentoxide (0.880 g, 8.01 mmol) was added under N2 to give a deep red solution and stirring was continued overnight at rt. The reaction mixture was poured into 50 mL of 10% HCl and extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulfate and concentrated in vacuo to give compound 477B as an oily red solid which was used directly in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C:19]2[CH:24]=[C:23]([C:25](=[O:30])[NH:26][CH:27]3[CH2:29][CH2:28]3)[CH:22]=[CH:21][C:20]=2[CH3:31])=[CH:6][CH:5]=1.O.[NH2:34][NH2:35]>CO>[CH:27]1([NH:26][C:25](=[O:30])[C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([N:14]3[CH:13]=[N:12][C:11]4[C:15]3=[N:16][CH:17]=[N:18][C:10]=4[C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:34][NH2:35])=[O:2])=[CH:5][CH:6]=3)[CH:24]=2)[CH2:29][CH2:28]1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2ncnc3c2ncn3-c2cc(C(=O)NC3CC3)ccc2C)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)NN)cc3)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of the 4-[9-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-9H-purin-6-yl]-benzoic acid methyl ester (65 mg, 0.15 mmol) in 1 mL of methanol was added 1 mL of hydrazine monohydrate. The reaction mixture was stirred at room temperature for 4 hours. The methanol was removed and then 2 mL of water was added. The product was collected by filtration to give a colorless solid (47 mg, 72%). HPLC tR=1.62 min; MS m/z 428 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH2:16])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[NH2:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(O)(CN)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A stirred mixture of 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the mixture was stirred at 80° C. oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 ml×3). The combined organic extracts were concentrated under reduced pressure to give 4-aminomethyl-1-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16](Br)=[N:15][C:14]=3[CH3:19])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:15][C:14]=3[CH3:19])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22]
Reactant: C1COCCN1
Reactant: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Temperature: 100 °C
Yield: 41.8 %

Procedure:
72 mg of 7-bromo-3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 mmol) and 66 mg of morpholine (0.76 mmol) and 97 mg of cesium carbonate (0.3 mmol) are put in 4 ml vial with 3 ml of dry THF. The vial is capped with a Teflon® lined cap and heated at 100° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 30 mg of the title compound. Yield 42%: mass spectrum (m/e): 479 (M+1); 1H-NMR (CDCl3): 3.87 (t, 4H, J=5.0 Hz), 3.55 (t, 4H, J=5.0 Hz), 3.45 (m, 1H), 2.70 (s, 3H), 2.44 (s, 3H), 2.40 (m, 2H), 2.18 (s, 3H), 2.01 (m, 2H), 0.88 (t, 6H, J=7.3 Hz).
Reaction SMILES: N12CCN(CC1)CC2.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C(OCC)C>[Cl:14][C:15]1[C:16]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
To a solution of 1,4-diazabicyclo[2.2.2]octane (DABCO, 680 mg, 6.06 mmol) in diethyl ether (20 mL) at −78° C. was added n-butyllithium (2.5M in hexanes, 3.0 mL) and stirring continued for 20 minutes. To this mixture was added 3-chloropyridine (700 mg, 6.16 mmol) as a solution in diethyl ether (5 mL). After 30 minutes, tert-butyl 4-oxo-1-piperidinecarboxylate (1.3o g, 6.52 mmol) was added as a solution in diethyl ether (1 mL). The reaction mixture was stirred at −78° C. for 2.5 hours then warmed to −50° C. and quenched with water. The mixture was allowed to warm to room temperature overnight. The layers were separated and the organic phase dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 20% to 99% ethyl acetate:hexanes) to provide the title compound (110 mg, 9% yield). 1H NMR (500 MHz, CDCl3) δ 1.38 (br d, 2H, J=13.7 Hz), 1.50 (s, 9H), 2.73 (ddd, 2H, J=13.1, 13.1, 5.3 Hz), 3.31 (br m, 2H), 4.09 (br m, 2H), 7.25 (m, 1H), 7.74 (dd, 1H, J=7.8, 1.3 Hz), 8.46 (dd, 1H, J=4.7, 1.6 Hz).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Br[CH2:8][CH2:9][CH2:10][Cl:11].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[Cl:11][CH2:10][CH2:9][CH2:8][N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1
Reactant: ClCCCBr
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OC1CN(CCCCl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
In a 25 mL round-bottomed flask were mixed with stirring azetidin-3-ol hydrochloride (available from Beta Pharma, 250 mg, 2.28 mmol) and 1-bromo-3-chloropropane (719 mg, 4.56 mmol.0) in acetonitrile (5 mL) to the suspension was added Cs2CO3 (1.86 g, 5.7 mmol.50). The mixture was stirred at 25° C. for 18 h, then diluted with 15 mL of EtOAc and filtered to remove solids. Filtrate was evaporated and residue purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane (developing TLC in an iodine chamber) to give 1-(3-chloropropyl)azetidin-3-ol (128 mg, 856 μmol, 37.5%) as a clear dense liquid. 1H NMR (CDCl3) δ: 4.25-4.53 (m, 2H), 3.36-3.68 (m, 4H), 2.82-3.04 (m, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.80 (quin, J=6.8 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1CN([P+](O[N:37]2N=[N:44][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[NH2:44])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield 4-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2-aminophenyl)benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.60 (s, 2H), 6.54-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-6.98 (m, 1H), 7.13 (d, J=7.58 Hz, 1H), 7.18-7.23 (m, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.48-7.54 (m, 1H), 7.65-7.70 (m, 1H), 7.93 (d, J=8.08 Hz, 2H), 8.46 (s, 1H), 9.60 (s, 1H). ESI-MS: m/z 343.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccccc1CBr

Procedure:
A mixture of 2-methylbenzophenone (9.8 g), N-bromosuccinimide (8.9 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (150 ml) was refluxed for 1 hour with light irradiation. The mixture was cooled, and then filtered to remove insoluble substances. The filtrate was concentrated to afford quantitatively the above-titled compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[S:3]1(=[O:19])=[O:18].[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([NH:20][C:21]2[S:22][C:23]([CH3:26])=[CH:24][N:25]=2)=[O:10])=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[S:3]1(=[O:19])=[O:18]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2ccc(C)cc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)S(=O)(=O)N(C)C(C(=O)Nc1ncc(C)s1)=C2O
Yield: 84.8 %

Procedure:
2.83 gm (0.01 mol) of methyl 2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.25 gm (0.011 mol) of 2-amino-5-methyl-thiazole were reacted in xylene analogous to Example 8, and 3.1 gm (84% of theory) of 2,7-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH2:30][CH2:31][CH2:32][OH:33].C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[N:11]=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:30][CH2:31][CH2:32][OH:33])=[O:27])=[CH:28][CH:29]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Reactant: NCCO
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)NCCO)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoic acid (100 mg) obtained in Step A of Example 231, 2-aminoethanol (0.022 mL) and triethylamine (0.050 mL) in DMF (3 mL) was added 2-(7-azabenzotriazol-1-yl)-1,1,3,3-hexafluorophosphate (137 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (105 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[Br:1][C:2]1[S:6][C:5]([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:14](=[O:16])[CH3:15])=[N:4][CH:3]=1
Reactant: Brc1cnc(Nc2ccccn2)s1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(c1ccccn1)c1ncc(Br)s1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a flask containing (5-Bromo-thiazol-2-yl)-pyridin-2-yl-amine (5-4, 4.58 g, 17.9 mmol was added 30 mL acetic anhydride. The suspension was then heated to 100° C. After about 1.5 hours, the acetic anhydride and acetic acid was removed under reduced pressure, heating the bath to 70° C. Two 70 mL portions of toluene were also added for azeotropic distillation. The product was obtained as a tan colored precipitate. 1H NMR (DMSO-d6): δ8.65 (d, 1H, J=3.9 Hz), 8.09 (t, 1H, J=8.6 Hz), 7.67 (d, 1H, J=8 Hz), 7.59 (t, 1H, J=6.6 Hz), 7.47 (s, 1H). mp 132-138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(C#N)(C)=O>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.O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: Cc1cccc(B(O)O)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 150 °C
Yield: 77.8 %

Procedure:
Alternatively, 1-(4-bromophenyl)-2,2,2-trifluoroethanol (0.98 g, 3.86 mmol), m-tolylboronic acid (0.63 g, 4.63 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.232 mmol Pd), Na2CO3 (0.90 g, 8.49 mmol), AcCN (10 mls), and H2O (10 mls) were combined and heated in the microwave at 150° C. for 10 minutes. The reaction was shown complete by TLC(CH2Cl2). The mixture was cooled, concentrated, slurried in CH2Cl2, filtered, and chromatographed over silica gel (CH2Cl2) to give 0.80 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 79%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:33]I.C(=O)=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC.O.C(OCC)C>[I:33][C:11]1[CH:10]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccc(N2CCOCC2)nc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Temperature: -35 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A solution of 28.4 g (108 mmol) 2,2-dimethyl-N-(6-morpholin-4-yl-pyridin-3-yl)-propionamide and 49 ml (324 mmol) N,N,N′,N′-tetramethylethylenediamine under argon in 600 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within 1 h, 202 ml (324 mmol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −35° C. overnight. After cooling again to −78° C., 37 g (146 mmol) iodine dissolved in 60 ml tetrahydrofuran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0° C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 15.6 g (37%) of the title compound as a light brown oil which crystallized upon standing at room temperature.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:15]=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:15]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.15 mL, 0.44 mmol) was added to a THF (1.8 mL) and MeOH (2 mL) solution of ethyl 3-(5-(5-methoxy-2-(((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (85 mg, 0.15 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (509 mg) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.28 mL) and then methanesulfonyl chloride (0.14 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water and extracted into dichloromethane. The combined organics were washed with brine, dried (MgSO4) and reduced in vacuo to yield methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[N:20]=[N:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1.FC1C=C(C=C(F)C=1)N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[Cl:74])[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[Cl:74][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=1[O:67][CH:64]1[CH2:63][CH2:62][N:61]([C:59](=[O:60])[CH2:58][NH:57][C:23]([C:21]2[N:20]=[N:19][N:18]([C:13]3[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([F:10])[CH:12]=3)[CH:22]=2)=[O:25])[CH2:66][CH2:65]1
Reactant: O=C(O)c1cn(-c2cc(F)cc(F)c2)nn1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cc(F)cc(F)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2cc(F)cc(F)c2)nn1
Reaction time: 0.03 h
Yield: 64.19 %

Procedure:
DIPEA (160.7 mg, 1.24 mmol) was added to a stirred solution of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3,5-difluoroaniline) (70 mg, 0.31 mmol) in DMF (2 mL) followed by HOBt (46.2 mg, 0.34 mmol) and EDCI (119 mg, 0.62 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (94.8 mg, 0.31 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected. The crude solid was stirred in a mixture of 30% EtOAc in hexane and MeOH (0.5 mL) for 1 hr and filtered to afford 95 mg (64.19% Yield) of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 476.12, 98.71%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 8.5 (t, 1H), 7.9 (m, 2H), 7.6-7.4 (m, 2H), 7.4-7.2 (m, 2H), 7.0 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8-3.6 (m, 2H), 3.6-3.4 (m, 2H), 2.1-1.8 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11]C[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.C1(=O)NCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]2=[O:15])=[O:7])=[CH:16][CH:17]=1
Reactant: O=C1CCCCCN1C(=O)c1ccc(Cl)cc1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccc(Cl)cc1

Procedure:
Synthesized as for N-(4-chlorobenzoyl)caprolactam (Example XXIX) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>C1COCC1>[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:15][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: CC(C)(C)CCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3.95 mL, 7.9 mmol, 2M solution in THF) to a solution of 3,3-dimethyl-butan-1-ol (960 CL, 7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction mixture with saturated aqueous NaHCO3 (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL) and wash the organic layer with brine (100 mL). Dry the combined organic extracts over MgSO4 and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g, 94%). GC-MS m/z: 204 (Me).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[N:36][C:35]=1[C:49](O)=[O:50])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[N:36][C:35]=1[C:49]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:50]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2C(F)(F)F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid (Example 19) gave 323. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81-7.73 (m, 3H), 7.70-7.64 (m, 1H), 7.43 (s, 2H), 4.74 (dd, J=11.0, 3.4 Hz, 1H), 4.50-4.30 (m, 1H), 4.19-3.89 (m, 2H), 3.76 (s, 3H), 2.06-1.97 (m, 1H), 1.91-1.79 (m, 1H), 1.76-1.66 (m, 2H). LCMS (ES+) m/z 499 (M+1).