Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:14][C:16](=[O:18])[CH3:17])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a 1 L 3-necked round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged 150 g (0.70 mol) of (4R,5R)-3-amino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester and 50 mL of dry CH2Cl2. The reaction mixture was cooled to −20° C. To the mixture was added, successively, acetyl chloride (60 mL, 0.84 mol) and pyridine (66.8 g, 0.84 mol) over 0.5-hour time intervals. After the additions, the mixture was stirred at −20° C. to 0° C. for 2 hours and then filtered to remove the pyridine.HCl salt. The filtrate was diluted with 200 mL of CH2Cl2 and washed 2× with aliquots of aq NH4Cl. The organic solution was treated with silica gel (50 g), MgSO4 (20 g) and charcoal (20 g), and stirred at room temperature for 0.5 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 166.5 g (93% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.85 (t, J=7.4 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 1.00 (d, J=7.0 Hz, 3H), 1.11 (m, 1H) 1.29 (t, J=5.8 Hz, 3H), 1.40-1.25 (m, 2H), 1.65 (m, 1H) 2.13 (s, 3H), 3.80 (m, 1H) 4.2-4.14 (m, 3H), 5.01 (s, 1H), 11.28 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2c(OC)cccc2OC)sc2ncccc12
Agent: Cl
Solvent: CO
Product: COc1cccc(OC)c1Cc1sc2ncccc2c1S(=O)(=O)Nc1onc(C)c1Cl
Yield: 38.4 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(2,6-dimethoxybenzyl)thieno[2,3-b]pyridine-3-sulfonamide (0.11 g, 0.19 mmoles), methanol (5 ml) and 4N HCl (1 ml). Recrystallization from EtOAc/hexanes provided 35 mg (39%) of the title compound as a white precipitate, m.p. 66-71° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1=NC2(CCOc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)N=C1N
Temperature: 100 °C
Yield: 14.4 %

Procedure:
6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (73 mg, 0.25 mmol, Intermediate 4), 3,5-dichlorophenylboronic acid (95 mg, 0.50 mmol) and K2CO3 (83 mg, 0.60 mmol) were mixed in dioxane (2 mL) and degassed by passing nitrogen through for 5 min. Then (1,1′-bis(diphenyl-phosphino)ferrocene)-dichloropalladium(II) (10 mg, 0.01 mmol) was added and the mixture was heated in a sealed vial at 100° C. overnight. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloro-palladium(II) (10 mg, 0.01 mmol) was added and heating continued in a microwave oven at 130° C. for 2×1 h. Purification by preparative HPLC gave the title compound (13 mg, 14% yield): 1H NMR (400 MHz, CDCl3) δ ppm 2.04-2.30 (m, 2H), 2.38 (s, 3H), 4.50-4.69 (m, 2H), 4.88 (br s, 2H), 6.69 (s, 1H), 6.98 (d, 1H), 7.22-7.35 (m, 4H); MS (ES+), m/z 360 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(-c2ccc(Cl)cc2)cn1
Yield: 78 %

Procedure:
2-Amino-5-bromopyridine (2) was reacted with 4-chlorophenylboronic acid (3) in dioxane/water in the presence of 2.2 equivalents of Na2CO3 and 1 mol % Pd(OAc)2 plus 1 mol % PdCl2(dppf).CH2Cl2 at 90° C. for 1.5 h. After cooling to room temperature the product (4) was precipitated as the HCl salt by adding HCl (25%, 6 equiv) followed by removal of dioxane under vacuum. The salt was filtered, digested in diethylether, filtered and then converted to the free amine by treatment with aqueous NaOH. After filtration, the product was isolated in 78% yield. Alternatively, the product has been isolated by chromatography in 83% yield. MS (Turbo Spray): 207 (52%), 205 (M+H+, 100%), 170 (9%).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8]([F:19])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(=O)C)[N:11]=[CH:10]2)(=O)C.O1CCCC1.Cl>CO>[F:19][C:8]1[C:7]([OH:6])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2
Reactant: CC(=O)Oc1ccc2c(cnn2C(C)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2[nH]ncc2c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
A 6N aqueous sodium hydroxide solution (5 ml, 30 mmol) was added dropwise to a solution of 1-acetyl-4-fluoro-1H-indazol-5-yl acetate (995 mg, 3.78 mmol) in methanol (5 ml)-tetrahydrofuran (5 ml) at room temperature, and the resulting mixture was stirred for 3.5 hours while being maintained at room temperature. The resulting reaction solution was adjusted to pH 5 to 6 by dropwise addition of a 1N aqueous hydrochloric acid solution (about 25 ml) and extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-fluoro-1H-indazol-5-ol (219 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:12]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: NC(N)=S
Product: COc1ccc(-c2csc(N)n2)cc1
Yield: 85.2 %

Procedure:
Using 4′-methoxyacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[CH:31]1(N)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: NC1CCCCC1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with cyclohexylamine ([108-91-8]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as brown oil. MS: m/e=327.3 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:3][CH2:2]1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.CO>N1C=CC=CC=1>[CH:19]1([S:22]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])[CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: c1cc2c(ncc3[nH]nc(C4CCNCC4)c32)[nH]1
Solvent: c1ccncc1
Solvent: CO
Product: O=S(=O)(C1CC1)N1CCC(c2n[nH]c3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of 1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.023 g, 0.095 mmol) in pyridine (0.5 mL) was added cyclopropanesulfonyl chloride (0.015 g, 0.105 mmol). The reaction was stirred at about 25° C. for about 1 h. MeOH (0.5 mL) was added to quench the reaction and the crude reaction mixture was purified by RP-HPLC (Table 2, Method p) to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a solid (0.004 g, 6.5%): LC/MS (Table 2, Method a) Rt=1.74 min; MS m/z: 346 (M+H)+, 344 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([I:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([I:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(I)ccc2c1O
Product: CCCCOC(=O)c1nc(Cl)c2cc(I)ccc2c1O

Procedure:
0.215 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester were added to 5 ml of POCl3 at room temperature. The mixture was refluxed for 3 h and POCl3 was removed under vacuum. The residue was dissolved in ethyl acetate and the solution was washed with satd. aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to give 0.205 g of a while solid: Proton NMR (200 MHz, chloroform-d) δ 11.91 (s, 1H), 8.67 (m, 1H), 8.10 (m, 2H), 4.49 (t, J=7 Hz, 2H), 1.95-1.75 (m, 2H), 1.60-1.39 (m, 2H), 1.00 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[CH2:8][CH2:7][C:6](=O)[C:5]=2[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.[BH4-].[Na+]>C(Cl)Cl.CO.O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]=[C:2]1[C:3]2[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=2[C:5]2[CH:6]=[CH:7][CH2:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: C=C1c2ccccc2C2=C(C(=O)CC2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CO
Product: C=C1c2ccccc2C2=C(CC=C2)c2ccccc21
Temperature: 45 °C
Yield: 68.1 %

Procedure:
To a stirred solution of the ketone 6 (1.0 g, 4.0 mmol) in methylene chloride/methanol (3/1 by volume, 40 mL) was added sodium borohydride (1.0 g, 27 mmol). The reaction was monitored by thin layer chromatography (tlc) for the disappearance of the starting ketone, 6. After 1 hr the reaction was worked up diluting with water (30 mL) and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield a yellow solid. The yellow solid as dissolved in benzene (50 mL) containing p-toluenesulfonic acid (10 mg) and heated to 45° C. The reaction mixture was monitored by tlc for the disappearance of the alcohol (45 min). The reaction was worked up by washing with saturated aqueous sodium bicarbonate solution (30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.66 g (68 percent) of the 8-methylene-1,8-dihydrodibenzo[e,h]azulene, 7, as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: ClCCCBr
Reactant: COc1ccc(C2Sc3cc(Cl)ccc3NC(=O)C2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCCCl)C(=O)[C@@H]2O)cc1
Yield: 106.3 %

Procedure:
8.395 g (25.0 mmol) of 2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (IV-1), 4.723 g (30.0 mmol) of 1-bromo-3-chloropropane (V-1) and 4.146 g (30.0 mmol) of K2CO3 were dissolved in 168 ml of acetone, and the mixture was refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure to give a residue, which was chromatographed on silica gel to give 10.96 g of cis-2-(4-methoxyphenyl)-3-hydroxy-5-(3-chloropropyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (III-1) from dichloromethane effluent parts. The obtained compound was recrystallized from ethyl acetate to give 9.146 g as colorless prisms in 88.7% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.58) (0.2 g, 0.45 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.14 g, 68%). MS (ISP) 461.3 [(M+H)+]; mp 162° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:26][CH2:25][C:14]3([N:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].C(O)C>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:26][CH2:25][C:14]3([N:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: NC1=NC2(CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)Nc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(C(=O)c3ccc(N)cc3)CC2)Nc2ccccc21

Procedure:
A suspension of 1-(4-Nitrobenzoyl)spiro[piperidine-4,2'(1'H)-quinazoline]4'-amine hydrochloride (Example 57)(181 mg, 0.45 mnmol) and 10% palladium on charcoal (18 mg, 10 mol%) in ethanol (20 ml) was stirred under 3 atrmospheres pressure of hydrogen for 20 h. The mixture was filtered and concentrated in vacuo. Purification by RP-HPLC eluting is with trifluoroacetic acid/water/methanol (1:90:10, increasing the gradient to 1:5:95) gave a yellow foam, MS (+FAB) 336 ([M+H]+), 1H NMR (d6 -DMSO) 10.64 (1H, s), 9.30 (1H, s), 8.75 (1H, s), 7.86 (1H, d, J 8.0 Hz), 7.78 (1H, s), 7.48 (1H, t, J 7.7 Hz), 7.42 (2H, d, J 8.2 Hz), 7.23 (2H, d, J 8.1 Hz), 6.94 (1H, d, J 8.3 Hz), 6.81 (1H, t, J 7.6 Hz), 4.05 (2H, br. s), 3.75 (2H, br. s), 3.63 (2H, br. s), 1.97 (2H, br. s), 1.84 (2H, br. s).
Reaction SMILES: CC1C=CC(C(N)C2C=CC=CC=2)=CC=1.[CH:16]1[C:28]2[CH:27]([CH2:29]OC(N[C@H](C(NC(B3OC(CCC(C)CC(O)=O)(C)C(C)(C)O3)CC)=O)CC(C)C)=O)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(NC(C)C)(C)C.C(OC(=O)C)(=O)C.CN1CCOCC1>CN(C)C=O>[CH2:29]=[C:27]1[C:28]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)O)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(C(N)c2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: C=C1c2ccccc2-c2ccccc21
Reaction time: 1.67 h

Procedure:
5 g (5.25 mmol) of 4-methylbenzhydrylamine resin were swollen in dimethylformamide and excess solvent was drained from the resin. The resin was then resuspended in dimethylformamide containing 3.4 g (5.48 mmol) of 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvaleric acid and 3 g (8.2 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. Thereto were added 3.0 ml (16.5 mmol) of diisopropylamine. The resulting mixture was agitated for 100 minutes and the resin was then drained and washed three times with dimethylformamide. The resin was then resuspended in dimethylformamide containing 5 ml (54.8 mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. The mixture was agitated for 30 minutes and the resin was then drained. The resin was then resuspended in dimethylformamide containing 5 ml (54.8 mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. The mixture was agitated for 30 minutes and the resin was then drained and washed three times with dimethylformamide, twice with ethyl acetate, twice with dichloromethane and twice with diethyl ether and then dried under a vacuum. After drying there was obtained 6 g of 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4-(RS),5,5-trimethyl-1,3 ,2-dioxoborolan-4-yl]-3(RS)-methyl-N-(RS)-(4-methylphenyl)-benzyl]valeramide-polystyrene conjugate as a pale brown solid (0.25 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nM).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 48 h

Procedure:
A mixture of 15 g of 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 8.3 g of K2CO3 and 7.18 ml of benzyl bromide in 80 ml of DMF is left with stirring at AT for 2 days. The reaction mixture is poured into water and extracted with AcOEt, an insoluble product is filtered off, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. This gives 14.6 g of the expected product.
Reaction SMILES: N1(C2C=CC=CN=2)CCCC1.Cl[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[N:20]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:35]=[CH:34][C:33]=3[S:42]([NH:45]C(C)(C)C)(=[O:44])=[O:43])=[CH:28][CH:27]=2)[CH:24]=[CH:23][N:22]=[CH:21]1>N1C=CC=CC=1>[CH2:16]([O:15][C:13]([NH:45][S:42]([C:33]1[CH:34]=[CH:35][C:36]([CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:27][CH:28]=1)(=[O:43])=[O:44])=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Reactant: CCCCOC(=O)Cl
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1ccc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 68 %

Procedure:
The crude product from step (d) above was dissolved in pyridine (2 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (36 mg, 0.024 mmol) and butyl chloroformate (276 μL, 2.23 mmol) were added to the mixture, which was then stirred for 30 h under N2 (g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl3:MeOH (10:1) as eluent yielded the title compound (66.7 mg, 0.142 mmol) in 68% yield (from 2-(4-imidazol-1-ylmethylphenyl)-4-iso-butyl-N-tert-butylbenzene-sulfonamide).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:9]([CH3:10])[CH3:8]
Reactant: CNC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ncc[nH]1
Temperature: 50 °C

Procedure:
To a two-necked round-bottomed flask equipped with a reflux condenser and a pressure-equalizing addition funnel, was added 2-imidazolecarboxaldehyde (6 g, 62.5 mmol) in MeOH (60 mL). To this suspension (ambient temperature) was added a solution of dimethylamine (40% aqueous, 60 mL) at a fast dropping rate (20 min). After the addition was complete, solid sodium borohydride (7 g, 186.8 mmol) was CAUTIOUSLY added portionwise over 45 min. Foaming occurred after each portion, and the internal temperature was allowed to maintain ˜50° C. without external cooling. The reaction mixture was then heated to 65° C. for 3 h and allowed to cool to ambient temperature for overnight. The reaction contents were concentrated in vacuo and the resultant residue was taken up in EtOAc (2×30 mL) washed with brine and with CHCl3 (4×100 mL). The EtOAc extract was discarded. The CHCl3 extract was dried over (NaSO4), filtered, and concentrated in vacuo to give 3.7 g of the desired product as a waxy solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[C:12]([F:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[C:12]([F:14])=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(F)c(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)c(Br)cc2s1
Yield: 90.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-5-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-27b: 0.3 g, 1.0 mmol) in THF (10 mL) was hydrolyzed with LiOH (87 mg, 2.04 mmol) and water (2 mL) to afford 250 mg of the product (yield 88%)
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:24]([C:26]1([OH:30])[CH2:29][CH2:28][CH2:27]1)#[CH:25]>>[F:23][C:3]1[C:2]([C:25]#[C:24][C:26]2([OH:30])[CH2:29][CH2:28][CH2:27]2)=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCC1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC3(O)CCC3)cc1-2
Yield: 25 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 1-ethynylcyclobutanol via General Procedure F to afford 26 mg (25%) of 9-fluoro-10-[2-(1-hydroxycyclobutyl)ethynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.