Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1SC=NN=1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[S:9][CH2:8]1>C1(C)C(C)=CC=CC=1.CN(C)C=O>[BrH:1].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:15][C:10]=2[S:9][CH2:8]1
Reactant: Brc1nncs1
Agent: c1cc2c(cc1CN1CCNCC1)SCO2
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Br

Procedure:
A solution of 4 g of 2-bromo-1,3,4 thiadiazole and 13 g of 1-[(2H)-1,3-benzoxathiol-5-yl methyl]piperazine in 200 ml of xylene and 10 ml of anhydrous dimethylformamide was refluxed for 3 hours. Then, the mixture was cooled, the crystals of 1-[(2H)-1,3-benzoxathiol-5-yl methyl]piperazine hydrobromide formed during the reaction were suctioned off, and the xylene filtrate was extracted several times with a 2 N solution of methane sulfonic acid. The acid layer was decanted off then rendered alkaline with an excess of potassium carbonate, and the raw base extracted with chloroform. The organic solution was washed with water, dried over dry potassium carbonate, and the solvent was evaporated off. There were obtained 8 g of an oily residue which was submitted to a high pressure liquid chromatography (Waters apparatus) in the system CH2Cl2 -methanol; 98-2.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([CH3:21])[C:14]=3[N:15]=2)=[CH:7][C:6]([CH2:22][CH3:23])=[C:5]([CH3:24])[N:4]=1.Cl.N1C=CC=CC=1>O>[CH3:21][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]3[C:3](=[O:2])[NH:4][C:5]([CH3:24])=[C:6]([CH2:22][CH3:23])[CH:7]=3)[O:12][C:13]=2[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: CCc1cc(CCc2nc3c(C)ccc(C)c3o2)c(OC)nc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(CCc2nc3c(C)ccc(C)c3o2)c(=O)[nH]c1C
Temperature: 140 °C
Yield: 42.7 %

Procedure:
A mixture of crude 2-methoxy-3-[2-(4,7-dimethylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridine (161 mg, 0.49 mmol) and pyridine hydrochloride (574 mg, 4.97 mmol) was warmed in a pre-heated oil bath at 140° C. for 15 minutes. The cooled residue was diluted with water and the product extracted into chloroform. This extract was dried (Na2SO4), filtered and the solvent evaporated. This residue was chromatographed on silica gel and eluted with a 0.5 to 2.5% methanol/chloroform gradient to yield 65 mg of pure product. The product was crystallized from diethyl ether to give 38 mg, m.p. 151.5°-153° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15].O>CN(C=O)C>[CH3:15][N:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(C#N)cnc21
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred solution of 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (2.88 g, 20.1 mmol) in DMF (40 mL) was added 60% NaH (2.41 g, 60.4 mmol). After 20 minutes, iodomethane was added in one portion (6.3 mL, 101 mmol) and the resulting mixture was stirred overnight. The following day, water was carefully added drop-wise to quench the remaining NaH before additional water was added (50 mL) causing precipitation of the product. Filtration and drying in vacuo afforded 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (3.16 g, 20.1 mmol, 100% yield) which was subsequently used without further purification. ES MS (M+H+)=158.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:22][C:21]([F:24])([F:23])[CH2:20]2)=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.OO.S([O-])([O-:29])=S>CO>[Cl:1][C:2]1[CH:7]=[C:6]([OH:29])[CH:5]=[N:4][C:3]=1[O:17][CH2:18][CH:19]1[CH2:22][C:21]([F:24])([F:23])[CH2:20]1
Reactant: [O-]S([O-])=S
Reactant: CC1(C)OB(c2cnc(OCC3CC(F)(F)C3)c(Cl)c2)OC1(C)C
Agent: OO
Solvent: CO
Product: Oc1cnc(OCC2CC(F)(F)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
3-Chloro-2-[(3,3-difluorocyclobutyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 4, 4.5 g, 12.5 mmol) was suspended in methanol (30 mL). Hydrogen peroxide (1.6 mL, 21.3 mmol) was added and the mixture stirred at room temperature under nitrogen for 16 hours. An aqueous solution of thiosulfite (10%, 10 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane) to afford the title compound (2.53 g, 81%):
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH:31]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:38][S:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Reactant: NS(=O)(=O)C1CCC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Temperature: 40 °C

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutanesulfonamide (Example 271G, 256 mg, 1.894 mmol) using the general procedure described in Step A of Example 272, albeit with an oil bath heated at 40° C. The crude product was purified by silica gel chromatography eluting with a gradient of EtOAc in hexanes. The product was obtained as a white powder (220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Br

Procedure:
Mitsunobu coupling of 4-Bromo-3-methyl-phenol and 4-(4-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as described in a previous example gave 4-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21].CO>CCCCCCC>[F:29][C:19]([F:18])([F:28])[CH:20]([NH:21][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(c1ccccn1)C(F)(F)F
Solvent: CCCCCCC
Solvent: CO
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (S)-(−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 392.1950 (M+H)+; αD20 (MeOH)=−91.1°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13](=[O:26])[CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][C:16]=1[O:17]C>CC(C)=O.Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:13](=[O:26])[CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][C:16]1=[O:17]
Reactant: CC#Cc1cc(C)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(C)c1
Agent: Cl
Solvent: CC(C)=O
Product: CC#Cc1cc(C)c(C2C(=O)CC(Cc3ccccn3)C2=O)c(C)c1

Procedure:
A solution of rac-2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone (0.5 g, 1.45 mmol) in acetone (10 ml) and 2N hydrochloric acid (5 ml) is heated at 80°C. under microwave irradiation for 40 minutes. Volatile solvents are removed in vacuo and residue is diluted with distilled water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic fractions are washed again with distilled water, brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography to afford rac-2-(2,6-Dimethyl-4-prop-1-ynylphenyl)-4-pyridin-2-ylmethylcyclopentane-1,3-dione.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([S:8](/[N:10]=[CH:11]/[C:12]1[N:16]2[CH2:17][C@H:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[F:37])[CH2:19][CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[N:14][CH:13]=1)=[O:9])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[C:4]([S:8]([NH:10][CH:11]([C:12]1[N:16]2[CH2:17][C@H:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[F:37])[CH2:19][CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[N:14][CH:13]=1)[CH3:1])=[O:9])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(/C=N/S(=O)C(C)(C)C)cnc21
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 117.5 %

Procedure:
Methylmagnesium bromide (0.24 mL, 0.71 mmol) was added to a solution of tert-butyl [(6S,9R)-3-{(E)-[(tert-butylsulfinyl)imino]methyl}-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (117 mg, 0.24 mmol) in tetrahydrofuran (4 mL) at 0° C. After 5 min, the mixture was warmed to ambient temperature. After 1.5 h, additional methylmagnesium bromide (0.24 mL, 0.71 mmol) was added. After 1.5 h, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous ammonium chloride and water. The mixture was extracted with ethyl acetate (3×). The organic extracts were washed with saturated brine, dried with magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) gave the title compound (144 mg). MS 511.2 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1)#[N:16]
Reactant: N#Cc1ccccc1CBr
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of (4-mercaptophenyl)boronic acid (0.847 g, 5.50 mmol), 2-(bromomethyl)benzonitrile (1.62 g, 8.25 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (2/1) and recrystallized from hexane/ethyl acetate to give the title compound (903 mg, yield 61%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](Cl)=[O:30]>>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29]([CH:25]4[CH2:26][CH2:27][CH2:28][O:24]4)=[O:30])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)C1CCCO1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C1CCCO1
Yield: 33.2 %

Procedure:
As described for Example 8, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to give a glass which is crystallized from ethyl acetate to give 0.22 g of crystals, m.p. 208°-214° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1
Temperature: 0 °C
Yield: 62.2 %

Procedure:
A solution of 7.5 g of 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester and 2.8 g of potassium hydroxide in 200 ml of 3A ethanol was refluxed for 4 hours. The mixture was poured into ice water and acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration, dried and recrystallized from ethanol to afford 4.2 g of 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid. Yield 65%. mp=241°-242° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CC1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O.SC1C=CN=CC=1.O(C)[Na].O=S(Cl)Cl.[NH2:51][C:52]([NH2:54])=[NH:53]>COCCOC>[NH2:53][C:52]([NH2:54])=[N:51][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: CO[Na]
Agent: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: Sc1ccncc1
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: Cc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 3 h

Procedure:
1.8 g of 2-methyl-4-(4-pyridylthio)-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with 4-mercaptopyridine in the presence of NaOCH3 at 180° followed by chlorination with SOCl2 ] dissolved in 20 ml of ethylene glycol dimethyl ether are added dropwise at room temperature to a solution of 1.5 g of guanidine in 20 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 25° for three hours. The mixture is then worked up in the customary manner and purified by chromatography on silica gel (ethyl acetate+15% methanol). N-Diaminomethylene-2-methyl-4-(4-pyridylthio)-5-methylsulfonylbenzamide is obtained in the form of a viscous oil, M+ +1(FAB)=365.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][N:35]=[CH:34][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1ccncc1F
Product: Cn1ncc(NC(=O)c2csc(-c3ccncc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoropyridin-4-yl)boronic acid gave 240. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.73-8.64 (m, 2H), 8.23 (dd, J=6.4, 5.0 Hz, 1H), 7.78 (s, 1H), 5.04-4.77 (m, 2H), 4.25-4.09 (m, 1H), 4.06-3.92 (m, 1H), 3.78 (s, 3H), 3.27-3.20 (m, 1H), 2.19-2.08 (m, 1H), 1.91-1.76 (m, 3H), 1.69-1.59 (m, 1H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[CH:31]1([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:39][C@H:38]([C:37]([O:36][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:12][CH:13]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:30]
Reactant: CS(=O)(=O)OCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Product: CC(C)C[C@H](NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1

Procedure:
From Intermediate 4J and L-Leucine cyclopentyl ester (Intermediate 8). LC/MS: m/z 534 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 8.47 (1H, d, J=7.7 Hz), 7.56 (2H, m), 7.45 (1H, d, J=9.6 Hz), 7.38-7.24 (4H, m), 7.15 (2H, m), 5.69 (1H, d, J=9.8 Hz), 5.09 (1H, t, J=5.3 Hz), 4.63 (2H, m), 4.31 (1H, m), 1.84-1.79 (2H, m), 1.66-1.53 (9H, m), 0.92-0.86 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([O:21]CC)=[O:20])[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([OH:21])=[O:20])[O:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CSCC1(c2ccc(Cl)cc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(CSCC(=O)O)(c2ccc(Cl)cc2)OC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
Ethyl ({[2-(4-chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetate (3.36 g, 9.36 mmol) was dissolved in THF (45 ml) and cooled to 0° C. LiOH (0.79 g, 18.8 mmol) in water (12 ml) was added and the mixture was stirred for 18 h at room temperature. The solvents were evaporated. The crude product was extracted between water and diethyl ether. The aqueous layer was acidified using 2M HCl to pH 6 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford 2.98 g (96%) of the title compound as an yellow oil. 1H-NMR (CDCl3, 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.95 (s, 2H), 3.34 (s, 2H), 3.45 (s, 4H), 7.4 (m, 4H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OC(C)C)(=O)C.[Cu]>[CH2:13]([O:12][C:10](=[O:11])[C:9]([F:16])([F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 67107.4 %

Procedure:
To the solution of 2-bromopyridine (18 mL, 0.2 mmol) and ethyl bromodifluoroacetate (27 g, 0.22 mol) in DMSO (70 mL) was added copper powder (29 g, 0.46 mol). The mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (100 mL). A solution of potassium dihydrogen phosphate (1.27 M, 150 mL) was added and stirred for 30 min. the copper salt was removed by filtration and washed with isopropyl acetate (100 mL). The filtrate layer was separated. The organic layer was washed with water (2×100 mL) and dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-40% methyl t-butyl ether in hexanes in 40 min) afforded difluoro-pyridin-2-yl-acetic acid ethyl ester (27 g, 68%) as a colorless oil. LC-MS m/e 202 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[F:32][C:33]1[CH:46]=[CH:45][C:36]2[C:37]([CH2:40][CH2:41][CH2:42][CH2:43]Cl)=[N:38][O:39][C:35]=2[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:43][CH2:42][CH2:41][CH2:40][C:37]3[C:36]4[CH:45]=[CH:46][C:33]([F:32])=[CH:34][C:35]=4[O:39][N:38]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Reactant: Fc1ccc2c(CCCCCl)noc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(CN2CCN(CCCCc3noc4cc(F)ccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
0.37 g of 1-[2-(4-Fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine obtained in Example 2 (4) was dissolved in 4.0 ml of dimethylformamide, and 0.19 g of N-ethyldiisopropylamine and 0.31 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)butyl chloride were added, followed by stirring at 120° C. for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.22 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)butyl]piperazine as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([C:17]1[C:18]([O:30][CH3:31])=[C:19](B(O)O)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(COC)OC>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:19]1[CH:20]=[C:21]([C:23]([CH3:24])([CH3:26])[CH3:25])[CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=1[O:30][CH3:31])[CH:11]=[CH:10]2
Reactant: Brc1ccc2cccc(Br)c2n1
Reactant: COc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: COCCOC
Product: COc1c(-c2ccc3cccc(Br)c3n2)cc(C(C)(C)C)cc1C(C)(C)C

Procedure:
A mixture of 2,8-dibromoquinoline (4.64 g, 16 mmol, prepared by the method of L. Mao et al., Tetrahedron Lett. 46 (2005) 8419), 3,5-di-tert-butyl-2-methoxyphenylboronic acid (4.3 g, 16 mmol), K2CO3 (5.6 g, 40 mmol), Pd(OAc)2 (0.08 g, 0.3 mmol), P(o-Tol)3 (0.2 g, 0.6 mmol), dimethoxyethane (40 mL) and water (10 mL) is refluxed for 8 h with stirring in an argon atmosphere. The mixture is then poured into water and extracted with CHCl3 (3×50 mL). The combined organic phase is washed with water and brine, and then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/CH2Cl24:1). Yield: 5.2 g (77%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=2[N:7]=[N:6]1.C(O)=[O:17]>O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:17])=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)nnn2CCCO
Solvent: O
Product: O=Cc1ccc2c(c1)nnn2CCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 500 mg (2.47 mmol) of 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazole-5-carbonitrile (Intermediate 18) and 550 mg of Ni—Al alloy 1:1 in 5.55 ml of 75% formic acid in water is stirred at 90° C. for 2.5 hr. After filtration and evaporation 10 ml of 2N NaOH and 10 ml of EtOH are added to the residue and the system is stirred at rt for 1.5 hr. The pH is made 6-7 by addition of 2N HCl and the system is extracted thoroughly with ethyl acetate. After washing with water, drying and concentrating, 0.35 g of 80% pure title compound (55% yield).