Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:9][C:10]=1[CH2:11][Br:18])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)sc1CBr
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of 5-methyl-2-phenyl-thiazole-4-carboxylic acid ethyl ester (7.76 g, 0.03 mol), N-bromosuccinimide (5.87 g, 0.03 mol) and benzoyl peroxide (761 mg, 3.30 mmol) in carbon tetrachloride (130 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (10.66 g); MS: (+) m/z 325.93, 328.00 (M+1, 79Br/81Br).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH:12][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:10][C:9]([C:13]([F:15])([F:16])[F:14])=[N:8]2)=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Yield: 104.5 %

Procedure:
According to the procedure described in Example 161C, to a solution of 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (2.237 g, 9.57 mmol) in THF (25 mL) and K2CO3 (2.48 g, 18.5 mmol) was added phenyl chloroformate (1.887 g, 12.1 mmol). The crude product was purified by silica gel chromatography with 5-20% EtOAc/hexane as eluants to afford phenyl 1-p-Tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (3.614 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 6H), 7.26 (m, 2H), 7.24 (m, 2H), 6.86 (s, 1H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13]C)=[O:12])=[C:6]2[C:10]=1[O:9][CH2:8][CH2:7]2.[OH-].[Li+].O>CO.O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([OH:13])=[O:12])=[C:6]2[C:10]=1[O:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1ccc(N)c2c1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)c2c1OCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
Methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (2.30 g, 11.90 mmol) was dissolved in 80 mL of the mixture solvent of methanol and tetrahydrofuran (V/V=1:1) followed by the addition of a 1 M solution of lithium hydroxide solution (47.6 mL, 47.60 mmol) in tetrahydrofuran. The reaction solution was heated to reflux for 5 hours, then cooled down to room temperature, stirred for 12 hours. The reaction solution was added with 20 mL of water and concentrated under reduced pressure. The resulting residue was added with 100 mL of water, extracted with ethyl acetate (50 mL×2), the combined aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 3 resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 22e (1.70 g, yield: 80.0%) as a gary solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH3:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(Br)cc(N)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A heterogeneous reaction mixture of 4-bromo-2-methoxy-6-nitrotoluene (500 mg, 2.032 mmol), acetic acid (20 ml), and iron (1135 mg, 20.32 mmol) was stirred at rt for 24 hr. Ethyl acetate was added, then the mixture was filtered through celite and the filtrate concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with further ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford the title compound. MS m/z: 218.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([S-:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: [S-]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Sc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium thiophenolate (2 g, 15 mmol) were mixed in DMF (12 ml) and then the mixture was stirred under heating at 100° C. for 7.5 hours. To the reaction mixture was added brine and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (228 mg, yield 89%).
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1)C1CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), Cs2CO3 (0.122 g, 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) was stirred at 70° C. for 2 h. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester as a solid (72 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)[C:12]([C:14]1[NH:15][C:16](=[O:36])[C:17]([O:34][CH3:35])=[C:18]2[C:23]=1[CH2:22][CH2:21][N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=1)[C:19]2=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[CH2:24][N:20]1[CH2:21][CH2:22][C:23]2[C:18](=[C:17]([O:34][CH3:35])[C:16](=[O:36])[N:15]3[CH2:40][CH2:39][CH2:38][CH2:37][N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12](=[O:13])[C:14]3=2)[C:19]1=[O:33]
Reactant: COc1c2c(c(C(=O)N(CCCCOS(C)(=O)=O)CCOCc3ccccc3)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 75 °C

Procedure:
To a mixture of N-[2-(benzyloxy)ethyl]-N-(4-methanesulfonyloxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (90 mg, 0.14 mmol) and cesium carbonate (53 mg, 0.16 mmol) in DMF was heated at 75° C. for 90 minutes. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:49]([NH:51][CH2:52][C:53]([OH:55])=[O:54])[CH3:50]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[CH2:49]([N:51]([C:18](=[O:20])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1)[CH2:52][C:53]([OH:55])=[O:54])[CH3:50]
Reactant: CCNCC(=O)O
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCN(CC(=O)O)C(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (14 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and ethyl glycine hydrochloride (40 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (95 mg, 0.187 mmol, 79%) as a colorless amorphous substance.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][C:29]=1[O:37][CH3:38])(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:35])[NH2:36])=[CH:30][C:29]=1[O:37][CH3:38])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)O
Reactant: COc1cc(C(=N)N)ccc1OS(C)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C(=N)N)ccc1OC(=O)CC(C)C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Into 40 ml of anhydrous pyridine, was dissolved 1.5 g of isovaleric acid. To the solution, while being cooled in ice, was added 3.7 g of DCC and the resulting mixture was stirred for 30 minutes. After addition of 3.9 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture was stirred overnight at room temperature. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate to precipitate colorless crystals. The crystals were washed with ethyl ether, dissolved in DMF, and recrystallized by adding ethyl ether. The crystals were further purified by recrystallizing from an ethanol-ethyl ether mixture to obtain 3.4 g of colorless flaky crystals of 4-amidino-2-methoxyphenyl isovalerate methanesulfonate.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.B([O-])=O.[Na+].P([O-])([O-])([O-])=O>C(O)(C)C>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=B[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)C1(c2ccccc2)CCC(O)CC1
Reaction time: 8 h
Yield: 81.3 %

Procedure:
3.35 g of 4-dimethylamino-4-phenylcyclohexanone were suspended in 25 ml of isopropanol; 620 mg of sodium boranate were added, while cooling with an ice bath, and stirring was carried out overnight at room temperature. 6.5 ml of phosphate buffer (pH 7, Merck-Darmstadt) were added dropwise and the mixture was concentrated. The residue was taken up in 10 ml of water and 20 ml of diethyl ether and rendered alkaline with potassium hydroxide. The phases were separated and extracted three times using 15 ml of diethyl ether each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 2.75 g of 4-dimethylamino-4-phenylcyclohexanol were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH2:30][CH3:31])[C:27]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)=[O:28])[CH3:25]
Reactant: CCN(CC)C(=O)Cl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: CCN(CC)C(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and diethylcarbamoyl chloride
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8].Cl>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][NH2:10])=[O:8]
Reactant: Cn1ccnc1C(=O)NNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccnc1C(=O)NN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2-[(1-methyl-1H-imidazol-2-yl)carbonyl]hydrazinecarboxylate (I45) (143 mg, 0.595 mmol) in 1,4-dioxane (1.5 ml) stirred under argon at room temp was added a solution of hydrochloric acid (4 M) in dioxane (2.232 ml, 8.93 mmol). The reaction mixture was stirred at RT for 48 hr, then evaporated in vacuo and the residue added to an SCX column and eluted with dichloromethane (100 ml) followed by 5% MeOH/DCM (50 ml), 10% MeOH/DCM (30 ml), and 2M NH3/MeOH (50 ml) to afford the required product as a chartreuse solid in 73.1 mg, which was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([Cl:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])c(Cl)c3)ccc2n1)C1CC1
Yield: 111.4 %

Procedure:
Using N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.92 mmol), 4-fluoro-2-chloro-1-nitrobenzene (315 mg, 1.79 mmol), dimethyl sulfoxide (4 mL) and cesium carbonate (675 mg, 2.07 mmol), and in the same manner as in Reference Example 101, the title compound (382 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([OH:27])[CH2:10][C@H:11]([C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH2:21][CH2:22]2)[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([OH:27])[CH2:10][C@H:11]([C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH2:21][CH2:22]2)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Agent: [Pd]
Solvent: CO
Product: CC(C)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Yield: 93 %

Procedure:
[(1S,2S,4R)-1-Benzyl-4-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-hydroxy-7-methyl-oct-6-enyl]-carbamic acid tert-butyl ester (D6) (1.61 g, 3.33 mmol) in methanol (30 ml) was hydrogenated over 10% Pd/C (300 mg) for 3.75 h. The catalyst was filtered and the filtrate evaporated to afford D7 (93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (70 mg, 0.2 mmol) in an analogous manner to Example 936 to afford an off white foam (81 mg, 80%). Mp: 171-4° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 8.57 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 6.88 (d, J=8 Hz, 1H), 3.74 (s, 7H), 3.23 (m, 1H), 2.89 (m, 2H), 2.77 (s, 6H), 2.70 (m, 2H), 2.60 (m, 2H), 2.41 (m, 2H), 2.12 (d. J=11 Hz, 2H), 1.77 (m, 1H), 1.36 (m, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1.[O:60]1[CH:65]([C:66]([O:68][CH2:69][CH3:70])=[O:67])[CH2:64][NH:63][C:62]2[CH:71]=[CH:72][CH:73]=[CH:74][C:61]1=2>O1CCOCC1.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[N:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[N:63]1[CH2:64][CH:65]([C:66]([O:68][CH2:69][CH3:70])=[O:67])[O:60][C:61]2[CH:74]=[CH:73][CH:72]=[CH:71][C:62]1=2
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CN(c2ccccn2)c2ccccc2O1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
In a sealable tube, tris(dibenzylideneacetone) dipalladium (0) (5.2 mg, 0.0056 mmol), (S)-BINAP (10.7 mg, 0.017 mmol), cesium carbonate (132 mg, 0.41 mmol), 2-bromopyridine (33 □L, 0.35 mmol), and ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 60 mg, 0.29 mmol) were dissolved in dioxane (2 mL). The reaction vessel was sealed and the suspension was heated at 100° C. for 20 h. The reaction mixture was cooled to ambient temperature, diluted with water (15 mL), and the product was extracted with dichloromethane (3×20 mL). The organic fractions were dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (15% to 25% EtOAc/hexane) afforded the title compound (46 mg, 0.16 mmol). MS m/z: 285 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]2[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.[NH2:14][C:15]1[C:20]2[CH:21]=[C:22](Br)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[CH:21]=[C:22]([C:2]3[CH:3]=[C:4]([CH:7]4[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]4)[S:5][CH:6]=3)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: N#CC1CCOC1c1cc(Br)cs1
Product: N#CC1CCOC1c1cc(-c2cc3c(N)ncc(C(N)=O)c3s2)cs1

Procedure:
87 was prepared from 2-(4-bromo-thiophen-2-yl)-tetrahydro-furan-3-carbonitrile 86 and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in a similar manner to that described in Example 18. 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (s, 1H), 7.90 (bs, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.26 (bs, 1H), 7.12 (s, 2H), 5.30 (d, J=7.49 Hz, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 2.49 (m, 1H), 2.33 (m, 1H). MS (EI) m/z (M+H+) 371.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:41]([F:44])([F:43])[F:42])[CH:27]=[C:28]2[C:32]=1[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:30]=[CH:29]2.[H-].[Na+]>CN(C)C=O>[C:16]1([C:3]2([CH2:2][O:1][CH2:23][C:24]3[CH:25]=[C:26]([C:41]([F:44])([F:42])[F:43])[CH:27]=[C:28]4[C:32]=3[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[N:30]=[CH:29]4)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.669 g, 2.3 mmol) and 7-(bromomethyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.94 g, 2.3 mmol) in dimethylformamide (7 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.119 g, 3.0 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12% EtOAc/Hex) gave 1.13 g (79%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.41 (d, J=0.9 Hz, 1H), 7.10-7.28 (m, 5H), 5.37 (s, 2H), 4.73 (s, 2H), 3.69 (bs, 2H), 3.45 (s, 2H), 3.39 (m, 2H), 3.01 (m, 2H), 2.13 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H), 0.77 (m, 2H), −0.11 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.0 142.7, 139.3, 134.7, 128.4, 127.1, 126.4, 125.6, 124.8, 124.6 (q, J=273 Hz), 123.5 (q, J=32 Hz), 122.1, 119.2, 79.4, 79.2, 79.0, 70.6, 66.1, 41.5, 40.3 (br), 32.2, 28.5, 17.8, −1.4. Mass spec.: 620.15 (MH)+.