Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 53.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-3-pyrrolidinol (47 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, yield 53%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([Cl:22])[CH:15]=2)[N:11]([CH3:23])[N:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:22])[CH:15]=2)[N:11]([CH3:23])[N:10]=1
Reactant: COc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To benzene (300 ml) are added the crude product of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-methoxyphenyl)-1-methyl-1H-1,2,4-triazole (70.5 g) and anhydrous aluminum chloride (80.0 g), which are heated under reflux for 3 hours with stirring. After cooling to room temperature, the reaction mixture is poured into ice water and extracted with toluene. The organic layer is washed with water, extracted with aqueous solution of 20% NaOH, and the aqueous layer is acidified by adding a concentrated sulfuric acid little by little while cooling with ice and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 64.2 g of desired compound.
Reaction SMILES: C1(C)C=CC(C=O)=CC=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=4[N:26]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.N1CCCCC1C[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2NC3C=CC(C(N)=O)=CC=3N=2)=[CH:48][CH:47]=1>>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=5[N:26]=4)=[CH:23][CH:24]=3)[CH2:12][CH2:11]2)=[CH:48][CH:47]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCNCC4)cc3)nc2c1
Agent: Cc1ccc(C=O)cc1
Product: COc1ccc(CN2CCC(CCOc3ccc(-c4nc5cc(C(N)=O)ccc5[nH]4)cc3)CC2)cc1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting p-anisaldehyde for p-tolualdehyde and 2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. HPLC (Method C): Rt=4.49. MS (ESI+): mass calcd. for C29H32N4O3, 484.25; m/z found, 485.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.17 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 4.13-4.11 (m, 2H), 3.73 (s, 3H), 3.41-3.38 (m, 2H), 2.94-2.85 (m, 2H), 1.99-1.96 (m, 2H), 1.86-1.79 (m, 1H), 1.79-1.71 (m, 2H), 1.47-1.36 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[N:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:12](=[O:14])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CC(c2ccccc2)CC(=O)N1c1ccncc1
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 19 g of 3-phenylglutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 2.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 2 days. The hot solution is decanted from some insolubles, cooled, filtered and the residue triturated with hot isopropanol, to yield the 4-phenyl-1-(4-pyridyl)-piperidin-2,6-dione melting at 229°-230°; the analogously prepared 4-(p-methoxyphenyl)-1-(4-pyridyl)-piperidine-2,6-dione melts at 168°-169°.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH2:11]Cl)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[P:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[Cl-:1].[Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH2:11][P+:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1ccc2scc(Cl)c2n1
Solvent: CC#N
Product: Clc1csc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: [Cl-]
Yield: 159 %

Procedure:
To a solution of 3-chloro-5-(chloromethyl)thieno[3,2-b]-pyridine (1.2 g, 5.5 mmol) in CH3CN (20 mL) was added P(Ph)3 (2.88 g, 11 mmol). The mixture was refluxed for 20 hr. and was then evaporated to dryness. Et2O (8 mL) was added. The mixture was stirred vigorously and the crystalline salt was filtered and washed with more Et2O to give. 2.1 g (81%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:36]1N=N[C:38]2[CH:39]=CC=C[C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(N[CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][O:74]1)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:36]([CH2:37][CH2:38][CH3:39])[CH:77]2[CH2:78][CH2:73][O:74][CH2:75][CH2:76]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCCNC1CCCCO1
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.06 g), TBTU (0.096 g) and HOBt (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by N-propyl-aminotetrahydropyran (0.033 g) as a solution in DMF (1 ml) after 20 min. The reaction mixture was stirred at room temperature for 20 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and saturated aqueous sodium bicarbonate and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a gum (0.07 g).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(-c2ccnn2C)csc1C(=O)NC(Cc1ccccc1)CN(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccnn2C)csc1C(=O)NC(CN)Cc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 1,1-dimethylethyl[2-({[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (51 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction was stirred over 5 h, concentrated and purified by reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) to afford the bis-TFA salt of the title compound. (16 mg, 41%): LC-MS (ES) m/z 355 (M+H)+. NMR (d4-MeOD, 400 MHz) δ ppm 7.64 (s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.28-7.21 (m, 1H), 6.30 (d, J=2.0 Hz, 1H), 4.58 (m, 1H), 3.69 (s, 3H), 3.27-3.13 (m, 2H), 3.07-2.93 (m, 2H), and 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:12](Br)=[CH:11][N:10]=[C:9]([S:14][CH3:15])[N:8]=1)=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(Cl)Cl>[CH3:3][C:2]1[C:12]2[CH:11]=[N:10][C:9]([S:14][CH3:15])=[N:8][C:7]=2[C:5](=[O:6])[NH:4][CH:1]=1
Reactant: C=CCNC(=O)c1nc(SC)ncc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CSc1ncc2c(C)c[nH]c(=O)c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of N-allyl-5-bromo-2-(methylthio)pyrimidine-4-carboxamide (Preparation 187, 24 mg, 0.083 mmol), diisopropylethyl amine (60 μl, 0.344 mmol) and PdCl2dppf.DCM (7 mg, 8.57 μmol) was dissolved in DMA (0.8 mL) and heated to 120° C. for 18 hours. Additional batches of base (60 uL) and catalyst (7 mg) were added and the mixture stirred at 150° C. for 8 hours. The mixture was diluted with DCM and quenched with brine. The aqueous layer was extracted with DCM and the combined organic layers washed with water, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 5% MeOH in DCM to give the title compound (8 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=2[F:9])[CH2:13][CH2:12]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1cccc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(Cl)c2F)CC1
Yield: 32.1 %

Procedure:
Combine 3-chloro-2-fluoroaniline (4.37 g, 30 mmol), 1-methylpiperidin-4-one (3.39 g, 30 mmol), sodium triacetoxyborohydride (5.26 g, 33 mmol), and acetic acid (5.4 g, 90 mmol) and stir at room temperature overnight. Partition the reaction mixture between dichloromethane and saturated aqueous NaCl containing NH4OH, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 2.34 g of the title compound (32% yield): mass spectrum (ion spray): m/z=243 (M+1); 1H NMR (CDCl3): 6.88 (ddd,1H), 6.63 (ddd, 1H), 6.56 (dd, 1H), 3.85 (br d, 1H), 3.28 (m, 1H), 2.80 (m, 2H), 2.30 (s, 3H), 2.13 (m, 2H), 2.04 (m, 1H), 1.53 (m, 2H). (file: mn4-b6k-284-2)
Reaction SMILES: [C:1]12([PH:11][C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCCCC)CCC.C1(C)C=CC=CC=1>[C:1]12([P:11]([C:12]34[CH2:19][CH:18]5[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]5)[CH2:21]3)[CH2:13]4)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CCCCCCBr
Reactant: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Agent: [Li]CCCC
Solvent: CCCCOCCCC
Solvent: Cc1ccccc1
Product: CCCCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
5.5 g (18 mmol) of di(1-adamantyl)phosphine were placed in 60 ml of di-n-butyl ether, and 20 ml of a 2.5 M solution of n-BuLi (50 mmol) in toluene were added. The mixture was refluxed for 45 min and cooled and 3.0 g (18 mmol) of 1-bromohexane were added dropwise. The mixture was refluxed for 30 min, cooled and washed with saturated ammonium chloride solution (3×), the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH:41]2[CH2:42][CH2:43][CH:37]1[CH2:38][NH:39][CH2:40]2)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH:37]2[CH2:43][CH2:42][CH:41]1[CH2:40][N:39]([CH2:20][C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)[CH2:38]2)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.153 g, 0.405 mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (95 mg, 0.445 mmol) gave 3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as an off white solid (0.186 g, 80%) [following purification by SiO2 chromatography, eluting with 0-5% MeOH/EtOAc]. MS (ESI) m/z 575.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C@H:13]([OH:15])[CH3:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][CH2:12][C@H:13]([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.75 (d, J=2.1, 1H), 8.09 (dd, J=8.0, 1.3, 1H), 7.95 (m, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.43 (dd, J=7.6, 1.4, 1H), 7.39-7.31 (m, 2H), 3.74-3.62 (m, 1H), 2.80-2.67 (m, 2H), 1.07 (d, J=6.3, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[F:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([F:32])[C:34]([OH:49])=[C:35]([F:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1
Yield: 86.2 %

Procedure:
Following general procedure F, tert-butyl cis-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (54 mg, 0.110 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.132 mmol) to afford the desired product (51 mg, 86%) as a light yellow solid: ESI MS m/z 538 [C30H33F2N3O4+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)[P:63]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:95])C=1>O1CCCC1.C(OCC)(=O)C.ClCCl>[P:63]([O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)([O:64][CH2:65][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)([O:72][CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)=[O:95]
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A solution of the compound of Example 111 (0.100 g, 0.124 mmol), dibenzyl diethylphosphoramidite (0.088 mL, 294 mmol), and 1H-tetrazole (0.045 g, 0.642 mmol) in tetrahydrofuran (1.2 mL) was stirred at room temperature for 12 hours. Dichloromethane (1.2 mL) was added and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (0.075 g, 0.434 mmol). After stirring for 30 minutes at −45° C., the reaction was diluted with ethyl acetate and washed twice with 10% Na2CO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with ethyl acetate, to give the title compound (0.104 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.Cl[C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41]([CH3:46])[N:40]=1.ClC1N=C(C)C=C(C)N=1>CC(O)=O>[CH3:46][C:41]1[N:40]=[C:39]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:18]4[N:22]=[CH:21][CH:20]=[N:19]4)=[O:9])[CH2:11]3)[CH2:15]2)[CH:44]=[C:43]([CH3:45])[N:42]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: Cc1cc(C)nc(Cl)n1
Solvent: CC(=O)O
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23, substituting (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Intermediate 21) for hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester and 4-chloro-2,6-dimethylpyrimidine for 2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd for C21H22FN7O, 407.19; m/z found, 408.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([NH:33][C:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=S)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[C:40]([O:39][C:37](=[O:38])[NH:36]/[C:34](=[N:33]\[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Mercuric chloride (41 mg, 0.15 mmol) was added to a mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol), bis-N-Boc thiourea (38 mg, 0.14 mmol) and triethylamine (0.45 mmol) in DMF (5 mL) at 0° C. After 1 h of stirring at 0° C., ethyl acetate was added. The resulting mixture filtered and the filtrate washed sequentially with water and brine then dried (Na2SO4) and concentrated. The resulting residue was purified by reverse-phase chromatography to yield Z-tert-butyl(((tert-butoxycarbonyl)imino)(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)methyl)carbamate (74 mg, MS m/z=587 (MH+).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.Cl([O-])(=O)(=O)=O.[CH2:18]1[C:25]2[CH2:24][CH2:23][CH2:22][N+:21]=2[CH2:20][CH2:19]1.Cl>CCCCC.CCOCC.C1COCC1.CCOCC>[N:9]1[CH:8]=[C:7]([C:25]23[CH2:24][CH2:23][CH2:22][N:21]2[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=1
Reactant: Brc1cncnc1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ncc(C23CCCN2CCC3)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
A solution of 1.7M tBuLi (1.6 mL, 2.6 mmol) in pentane was added to 5-bromopyrimidine (190 mg, 1.2 mmol) in Et2O:THF (1:1, 12 mL) at -100° C. After stirring for 10 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol) was added to the reaction slurry, and stirring was continued for 30 minutes. The reaction mixture was then allowed to warm to 0° C. and stir for 1 hour. A solution of 2N HCl was added, and the reaction mixture was poured over Et2O and the phases separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (40 mg, 18%). MS (CI/NH3) m/e: 190 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.60-1.73 (m, 2H), 1.82-2.11 (m, 6H), 2.66-2.75 (m, 2H), 3.15-3.21 (m, 2H), 8.85 (s, 2H), 9.05 (s,1H).