Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH2:43][CH2:44][CH2:45][OH:46]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCO
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.016 mL (0.20 mmole) of 3-amino-propan-1-ol in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-hydroxy-propyl)-3-methoxy-benzamide (I-41) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[C:23]2[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=2[N:15]=[CH:14]1)[CH2:2][CH3:3].C[Si](Cl)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31].[NH4+].[OH-]>N1C=CC=CC=1.O>[C:29]([NH:21][C:20]1[NH:19][C:17](=[O:18])[C:16]2[N:15]=[CH:14][N:13]([C:23]=2[N:22]=1)[C@@H:6]1[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]1[O:4][CH2:1][CH2:2][CH3:3])(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2'-O-Propylguanosine (3.6 gm) in pyridine (50 ml) was cooled in an ice bath and trimethylsilyl chloride (8.4 ml, 6 eq.) was added. The reaction mixture was stirred for 30 min and isobutyryl chloride (5.8 ml, 5 eq.) was added. The solution was stirred for 4 hours during which it was allowed to warm to room temperature. The solution was cooled, H2O added (10 ml) and the solution was stirred for an additional 30 mins. Concentrated NH4OH (10 ml) was added and the solution evaporated in vacuo. The residue was purified by silica gel chromatography using 10% MeOH/CH2Cl2 to elute the product. Product-containing fractions were evaporated to yield 2.5 g of product as a foam. An analytical sample was re-chromatographed on silica and eluted with CH2Cl2 →6% MeOH/CH2Cl2. 1H NMR (DMSO-d6) δ0.75 (t, 3, CH3), 1.13 [d, 6, CH(CH3)2 ], 1.4 (m, 2, CH2), 2.75 [m, 1, CH(CH3)2 ], 3.52 (m, 6, OCH2), 3.36 and 3.6 (ABX, 2, H-5'), 3.95 (m, 1), 4.26 (m, 1), 4.33 (m, 1), 5.07 (t, 1, 5'-OH), 5.18 (d, 1, 3'-OH), 5.9 (d, 1, H-1'), 8.25 (s, 1, H-8), 11.65 (br s, 1, NH) and 12.1 (br s, 1, NH). Anal. Calcd. for C17H25N5O6.1/2H2O: C, 50.49; H, 6.48; N, 17.32. Found: C, 50.81; H, 6.62; N, 17.04.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].P(Br)(Br)[Br:12]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10]
Reactant: Cc1cccc(CO)c1C
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(CBr)c1C

Procedure:
A mixture of 1-hydroxymethyl-2,3-dimethylbenzene (ref) (5 g) and phosphorous tribromide (1.16 ml) in benzene (50 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene, washed with water, dried (MgSO4) and evaporated. Yield 7 g.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][OH:4].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>C1COCC1.C([O-])(O)=O.[Na+]>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([C@H:2]2[CH2:3][O:4][C:22](=[O:23])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@H](CO)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N[C@@H](c2ccc(-c3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of (S)-2-amino-2-(biphenyl-4-yl)ethanol (171 mg, 0.802 mmol) in THF (12 mL) under argon atmosphere was added CDI (132 mg, 0.814 mmol). The solution was stirred at room temperature for 2 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with 0.5M aqueous HCl solution (30 mL), brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM and concentrated under reduced pressure to provide crude (S)-4-(biphenyl-4-yl)oxazolidin-2-one (156 mg) as a beige solid, which was used without further purification. LCMS m/z 240.1 (M+H)+, Rt 0.80 min.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Br)cc1
Yield: 88 %

Procedure:
A solution of 4-bromobenzylsulfonyl acetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 88% yield.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28].ClCCl>CN(C=O)C>[O:5]=[C:4]1[CH2:3][CH2:2][C:1](=[O:6])[N:24]1[C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:10][C:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([CH3:29])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N3C(=O)CCC3=O)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)O
Reaction time: 48 h
Yield: 99.8 %

Procedure:
Succinic anhydride (3.20 g, 32.0 mmol) was added to a 100° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 2.00 g, 6.39 mmol) in DMF (20 mL). After 2 days, the reaction mixture was concentrated under reduced pressure to give an off-white solid. The solid was stirred with 100 mL of dichloromethane and was isolated by filtration. The filtrate was concentrated, stirred with dichloromethane (25 mL), and filtered to yield additional solid. The combined solids were dried under vacuum to give 3.16 g of 4-({2-[4-(2,5-dioxopyrrolidin-1-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoic acid as a white solid that was used without further purification.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 54.2 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-acetyl-4-piperidinecarboxylic acid (5.1 g) and 1,8-diazabicyclo-[5.4.0]-undec-7-ene (4.6 g), and after successive recrystallization in a mixture of acetone and water (2:1 by volume) and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-acetyl-4-piperidinecarboxylate (7.5 g), m.p. 101° C., is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C@H:4]1[CH2:7][C@H:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:15]([I:18])[CH:16]=3)[C:11](=[O:23])[C:10]2=[O:24])[CH2:5]1)[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[Mg]I.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:11]1([OH:23])[C:12]2[C:17](=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[C:19]([F:21])([F:20])[F:22])[N:9]([CH2:8][C@H:6]2[CH2:5][C@H:4]([N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:7]2)[C:10]1=[O:24]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 1-1 (3.13 g, 6.52 mmol) in tetrahydrofuran (65 mL) was added dropwise a solution of 2,4-dichlorophenylmagnesium iodide (9.78 mmol) in ether (19.6 mL) at −78° C. The mixture was stirred for 1 hour, and to the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 20/1 to 10/1 to 5/1) to give the titled compound (2.95 g, 86%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)[C:29]#[N:30].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:33]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][N:36]=3)=[C:26]([O:25][CH3:24])[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: COc1cc(C#N)ccc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.75 g), 3-methoxy-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (3.03 g), anhydrous iron (III) chloride (1.70 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent and washed with hexane to give 2.80 g of desired compound.
Reaction SMILES: [Cl:1][C:2]1C(C)=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[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[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1OC(=O)C)(=[O:10])=[O:9].C([SiH]([CH2:47][CH3:48])CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:47]([CH3:48])=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[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:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:10])=[O:9]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3ccccc3c2OC(C)=O)sc2ncccc12
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Yield: 65 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(α-acetoxynaphthylmethyl)thieno[2,3-b]pyridine-3-sulfonamide (97 mg, 0.16 mmoles), CH2Cl2 (3 ml), triethylsilane (0.25 ml, 1.6 mmoles) and boron trifluoride etherate (0.19 ml, 1.6 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 58 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[N:16]([CH3:15])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CN1N=C(c2ccc(Cl)cc2)CCC1=O

Procedure:
To a 250 ml flask equipped with magnetic stirrer and reflux condenser was charged 10 g of 3-(4-chlorobenzoyl)-propionic acid, 250 ml of absolute ethanol, and 2.5 ml of methyl hydrazine. The reaction was refluxed for 3 hours and cooled to yield a solid which was collected by vacuum filtration, washed with 50 ml of hexane, and air dried. Isolated 9.5 g of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:14]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:23](=[O:24])[C@@H:22]3[CH2:26][CH2:27][CH2:28][N:21]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
5.00 g of 1-Amino-6-aminomethyl-isoquinoline and 6.20 g Boc-L-proline were dissolved in 88 mL DMF. 10.6 g of TBTU was added followed by a dropwise addition of N-methylmorpholine. Stirring was continued for 1 h at ambient temperature and the solvent was removed i.vac. The residue was extracted with 5% aqueous NaHCO3 solution and with ethyl acetate. The organic layer was separated and dried (NaSO4). The solvent was removed to give 10.7 g (quant.) of N-(1-Amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-prolinamide as an oil. Without purification, the compound was dissolved in 50 mL dichloromethane and 25.0 mL trifluoroacetic acid was added. Stirring was continued for 16 h and the solvent was removed i.vac. The residue was dissolved in methanol, the solvent was removed i. vac. And the residue was triturated with diethyl ether. The crystalline material was collected to give 12.9 g (89%) of N-(1-amino-isoquinolin-6-ylmethyl)-prolinamide. M.p. 140-142° C..
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH:11]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1C1=CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 3-nitro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (1.0 equiv.) in 20% TFA in CH2Cl2 (0.2 M) was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was dissolved with ethyl acetate (200 mL), and washed with sat NaHCO3 (30 mL), and sat NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enone (85%). The crude product was used to next step without further purification. LC/MS (m/z): MH+=218.9, Rt=0.60
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[S:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and benzothiophene-2-boronic acid (153 mg, 0.85 mmol) the subtitle compound was obtained (200 mg, 15%). MS 403.1 m/z (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:95])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:92])([CH3:91])[CH2:89][OH:90])[CH2:83][C@H:82]3[CH3:94])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:52]=[CH:51][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:91])([CH3:92])[CH2:89][OH:90])[CH2:83][C@H:82]5[CH3:94])=[CH:79][CH:80]=4)=[O:95])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:55][CH:54]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)CO)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)CO)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (37.6 mg, 0.17 mmol) in DMA (1 mL) was added HATU (65.9 mg, 0.17 mmol). The reaction mixture was stirred for 15 min and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide 3HCl (100 mg, 0.12 mmol; Preparation 34) was added followed by DIPEA (0.10 mL, 0.58 mmol) and the reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (4 mL) and purified by reverse phase HPLC. Fractions containing the desired compound were combined and lyophilized to provide the di-TFA salt of the title compound (65.2 mg) as a white powder. Impure fractions were lyophilized, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide additional di-TFA salt of the title compound (75 mg total, 55% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O9 955.37. found 955.8.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:1]([N:8]([C@H:9]1[C@H:10]([OH:14])[CH2:11][O:12][CH2:13]1)[C:24](=[O:25])[CH2:23][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1COC[C@H]1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N(Cc1ccccc1)[C@@H]1COC[C@H]1O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(benzylamino)tetrahydrofuran-3-ol (4.1 g, 21.2 mmol) in CH2Cl2 (40 mL) at −40° C. was added triethylamine (5.9 mL, 42.4 mmol) followed by dropwise addition of 2-chloroacetyl chloride (1.6 mL, 21.2 mmol). The reaction was stirred at −40° C. for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 100% EtOAc/hexanes afforded trans-N-benzyl-2-chloro-N-(4-hydroxytetrahydrofuran-3-yl)acetamide. MS APCI calc'd for C13H16ClNO3 [M+H]+ 270. found 270.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19]
Reactant: CN(C)CCN
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCN(C)C)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.9 %

Procedure:
To a stirred solution of N,N-dimethylethylenediamine (1.04 g, 11.8 mmol) in tetrahydrofurane (14 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) and subsequent crystallization (dichloromethane/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (1.07 g, 89%) as a white solid. MS (ISP) 305.1 [(M−H)−]; mp 143° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([N:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH:17]2[CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][CH:16]12)#[CH:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:29][N:26]1[CH2:27][CH2:28][C:16]2[N:15]([C:13]#[C:14][C:2]3[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)[C:23]3[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[C:17]=2[CH2:25]1
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CNC(=O)c1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-fluoro-N-methyl-benzamide (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine) palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (475 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using silica (100-200 mesh) and 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, free base) δ (ppm): 8.10 (t, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 7.18 (m, 2H), 6.70 (bs, 1H), 3.95 (m, 2H), 3.20 (m, 4H), 3.05 (d, 3H), 2.80 (s, 3H), 2.42 (s, 3H).