Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][Si:12]([CH3:15])(Cl)Cl.O>O1CCCC1.C([Li])CCC.CCCCCC>[CH3:11][Si:12]([CH3:15])([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH3:1])[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1=Cc2ccccc2C1[Si](C)(C)C1C(C)=Cc2ccccc21
Reaction time: 1 h
Yield: 68 %

Procedure:
In a 500 ml glass reactor, 4.3 g (33 mmole) of 2-methylindene was dissolved in 80 ml of tetrahydrofuran, to which 21 ml of 1.6M n-butyllithium in hexane was slowly added under cooling. After the mixture was stirred at room tempearture for 1 hour, it was cooled again, and 2.1 g of dimethyldichlorosilane was added dropwise. After the mixture was stirred at room temperature for 12 hours, 50 ml of water was added, and the organic phase was separated and dried to give 3.5 g of dimethylbis(2-methylindenyl)silane.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[S:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
L-alanine (100 g; 1.11 moles) was dissolved in 2.25 L of 1N sodium hydroxide (aq), cooled to 5° C. and stirred while a solution of p-toluenesulfonyl chloride (218 g; 1.11 moles) in 450 mL of toluene was added slowly. The mixture was stirred at ambient temperature for 20 hr. The layers were separated and the chilled aqueous layer acidified to pH 1 with concentrated hydrochloric acid. The white solid title compound was collected by filtration, washed with water and dried. Yield 178.5 g (66%) mp 134°-5° C. IR (CHCl3) cm-1 1726, 1340, 1165, 1095; 1H NMR (DMSO-D6) δ 1.20 (d, J=7, 3H), 2.40 (s, 3H), 3.85 (p, J=8, 1H), 6.4 (br d, 1H)(CO2H), 7.41 (d, JAB =8, 2H) and 7.75 (d, JAB =8, 2H) [center of pattern: 7.58; ΔVAB =20.49 Hz], 8.03 (br d, J=8, 1H)(NH).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In addition, synthesis was also performed according to the below-described method using 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (344.1 g, 1.28 mol) synthesized in Reference Example 4 and 1-(4-methoxyphenyl)piperazine (164 g, 853 mmol). That is, 1-(4-methoxyphenyl)piperazine (51.5 g, 268 mmol), palladium acetate (3.01 g, 13.4 mmol), BINAP (12.5 g, 20.1 mmol) and sodium tert-butoxide (38.6 g, 402 mmol) were added to a solution of toluene (775 mL) containing 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (108 g, 402 mmol), and the mixture was heated to reflux under argon atmosphere for 7 hours. After cooled to room temperature, water (775 mL) was added to the reaction solution for distribution. The organic layer was washed with saturated saline (515 mL) and dried using anhydrous magnesium sulfate, and after that, the solvent was removed under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane-ethyl acetate 98:2) and then silica gel column chromatography (hexane-ethyl acetate 100:0-94:6) to give a crudely purified product of the title compound as a yellow solid (68.0 g). Similarly, a crudely purified product of the title compound (136.6 g) was obtained from 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (213 g, 791 mmol) and 1-(4-methoxyphenyl)piperazine (101.5 g, 528 mmol). The obtained crudely purified products were put together and suspended in ethanol (2.3 L). This suspension was stirred at 65° C. for 30 minutes. After cooled to room temperature, it was further stirred for 1 hour, and crystals were collected by filtration to give a crude crystal of the title compound (181 g). Similarly, a crude crystal of the title compound was obtained from 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (23.1 g, 85.8 mmol) and 1-(4-methoxyphenyl)piperazine (11.0 g, 57.2 mmol). The obtained crude crystals were put together and recrystallized from acetone (2.82 L)/water (940 mL) to give 176 g of the title compound as a colorless crystal (yield: 54%). Melting point was 152 to 155° C.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56]([O:58]C)=[O:57])[CH2:52][CH2:51]1>>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:15]2[C:16]([CH3:27])([CH3:26])[C@H:17]3[C@:12]([CH3:37])([CH2:13][CH:14]=2)[C@@H:11]2[C@:20]([CH3:25])([C@@:21]4([CH3:24])[C@H:8]([CH2:9][CH2:10]2)[C@H:7]2[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]2([NH:5][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][CH:53]([C:56]([OH:58])=[O:57])[CH2:54][CH2:55]2)[CH2:23][CH2:22]4)[CH2:19][CH2:18]3)=[CH:36][CH:35]=1)([OH:34])=[O:33]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1CCN(CCCl)CC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methyl 1-(2-chloroethyl)piperidine-4-carboxylate hydrochloride (prepared as described below) as the alkylating reagent in Step 1. The product was isolated as a white solid (8 mg, 83%). LCMS: m/e 685.6 (M+H)+, 2.33 min (method 10). 1H NMR (400 MHz, METHANOL-d4) δ 7.94 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 5.31 (d, J=4.5 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.48-3.36 (m, 5H), 3.12-2.88 (m, 2H), 2.79-2.69 (m 1H), 2.68-2.60 (m, 1H), 2.24-2.11 (m, 4H), 2.11-2.00 (m, 4H), 1.97-1.81 (m, 3H), 1.77 (s, 3H), 1.81-1.71 (m, 2H), 1.70-1.46 (m, 10H), 1.45-1.27 (m, 4H), 1.21 (s, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[C:9]1=[O:21]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1-n1ccc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccncc1N1CCc2ccc(N)cc2C1=O

Procedure:
Using analogous reaction conditions as described in Example 24, 2-(4-methyl-pyridin-3-yl)-7-nitro-2H-isoquinolin-1-one (I-24b: 120 mg, 0.4240 mmol) in methanol (10 mL) and acetic acid (0.1 mL) was reduced using Pd/C (40 mg) at 50 PSI in a Parr hydrogenator at room temperature for 3.30 hours.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1>O1CCCC1.CCOCC>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]([CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]2)([OH:20])[CH2:15]1
Reactant: Cc1ccnn1C
Reactant: CC1(C)CCCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (2.5 M, 12.48 mL) in tetrahydrofuran (40 mL) was cooled to −78° C. and a solution of 1,5-dimethyl-1H-pyrazole (3.00 g) in tetrahydrofuran (3 mL) was added dropwise. After stirring for 1 hour, a solution of 3,3-dimethylcyclohexanone (3.94 g) in tetrahydrofuran (3 mL) was added dropwise and the reaction allowed to warm to 0° C. After stirring for 1 hour, the reaction was diluted with ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 25% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CCOCC>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphoshoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH:5]([CH3:16])[C:4]=2[CH:3]=1.[OH-].[K+].O.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CS(C)=O.ClCCl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:35])([CH3:16])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(CCCCN2C(=O)c3ccccc3C2=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
2,7-dibromo-9-methyl-9H-fluorene (10.0 g, 29.58 mmol) was dissolved in 50 mL DMSO under nitrogen. To mixture was added KOH (2.01 g, 35.79 mmol), water (1.5 mL), N-(4-bromobutyl)phthalimide (9.93 g, 35.2 mmol), and stirred reaction at room temperature for 2.0 hours, then at 50° C. for 3.0 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with brine (2×), and water. Removal of solvent yield a solid, which was purified by column chromatography (7:3, hexanes:EtOAc) to yield white solids (3.08 g, 20%). 1H NMR (500 MHz, CDCl3): δ=7.81-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.48-7.51 (m, 4H), 7.41-7.44 (dd, 2H), 3.46-3.49 (t, 2H), 2.00-2.04 (p, 2H), 1.47-1.49 (m, 2H), 1.45 (s, 3H), 0.65-0.68 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[N:20]([CH2:21][CH2:22][O:23][CH3:24])[N:19]=[N:18][N:17]=1.O.Cl>N1C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[N:20]([CH2:21][CH2:22][O:23][CH3:24])[N:19]=[N:18][N:17]=1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Reactant: COCCn1nnnc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COCCn1nnnc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
176 mg (0.75 mmol) of 2-chloro-4-(methylsulfonyl)benzoyl chloride, 145 mg (1.0 mmol) of 5-amino-1-(2-methoxyethyl)tetrazole in 2 ml of pyridine are stirred at 60° C. for 12 h. 0.1 ml of water is then added, the mixture is stirred at 60° C. for 30 min and EA and 2N HCl are added. The organic phase is separated off and washed with 2N HCl and brine, dried over Na2SO4, concentrated and purified by RP—HPLC (acetonitrile/water). Yield 66 mg (23%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:33])[CH3:32])=[O:29]>ClCCl>[Cl:33][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH3:32]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (428 mg, 1.51 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.33 mL, 3.02 mmol) and 1-chloroethyl chloroformate (0.164 mL, 1.51 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (40) as a mixture of two diastereomers (530 mg, 100%), which was used without further purification in the following example. 1H—NMR (CDCl3, 400 MHz): δ 0.87 (m, 6H), 1.13 (m, 2H), 1.63 (m, 1H), 1.76 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.10 (m, 1H), 3.27 (m, 1H), 5.11 (br.s, 3H), 6.53 (q, 1H), 7.33 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:5]=2[N:6]=1.[BH4-].[Na+]>CS(C)=O.O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[CH:7]([OH:19])[C:5]=2[N:6]=1
Reactant: CCCc1ccc2c(=O)c3nc(C)sc3ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product from step (x) (3.1 g) in dry dimethylsulphoxide (30 ml) and dry 1,4-dioxane (90 ml) was added sodium borohydride (0.7 g). After stirring at room temperature for 24 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, then brine. The organic layer was collected and dried over magnesium sulphate and solvent removed under reduced pressure to leave a pale yellow gum.
Reaction SMILES: FC(F)(F)S(O[CH:7]1[C:12]([CH2:13][CH:14]2[CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:11][CH:10]=[CH:9][NH:8]1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]12[CH2:18][CH:14]([CH:15]=[CH:16]1)[CH2:13][C:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(OC1NC=CC=C1CC1CC=CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C1=CC2CC1Cc1cccnc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
To a solution of 3-(cyclopent-3-en-1-ylmethyl)-1,2-dihydropyridin-2-yl trifluoromethanesulfonate (Preparation 26, 3.1 g, 10.1 mmol) in dimethylformamide (20 ml) stirred under nitrogen was added 1,3-bis(diphenylphosphino)propane (0.334 g, 0.8 mmol), triethylamine (1.52 g, 16.6 mmol) and palladium (II) acetate (0.072 g, 0.32 mmol). The reaction mixture was warmed to 100° C. and stirred for 18 h. Triethylamine (1 ml) was added and the reaction mixture was warmed to 110° C. for a further 6 h. The reaction mixture was cooled and poured into saturated brine solution (50%, 75 ml), and the product was extracted with ethyl acetate (4×30 ml). The combined organic extracts were washed with water (2 times), sodium hydrogen carbonate solution and brine before drying (Na2SO4) and concentrating in vacuo. The crude oil was purified by flash chromatography eluting with ethyl acetate:hexane (15:85) to give a colourless oil (1.07 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:41])=[C:21]([C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:25]=[CH:26][CH:27]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:41])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)c(C)sc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCNCC4)c3)c(C)sc2n1
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[3-(4-{[(3-chlorophenyl)sulfonyl]amino}-2,6-dimethylthieno[2,3-b]pyridin-3-yl)phenyl]-1-piperazinecarboxylate (60 mg, 0.098 mmol) (Example 31) in DCM (2 mL) was added 4M HCl in dioxane (0.122 mL, 0.489 mmol) and the mixture stirred for 3 h. Additional 4M HCl in dioxane (2.446 mL, 9.78 mmol) was then added and the mixture stirred overnight. Aqueous NaOH (5M) was then added to the solution dropwise until it was basic. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by MDAP (acidic conditions) and further purification using HPLC (CHIRALPAK AD (250×20 mm-10 micron); isohexane/ethanol gradient, 18 mL/min) afforded the title compound (12.7 mg). LCMS (A) m/z: 513 [M+1]+, Rt 0.93 min (basic), Rt 1.01 min (acidic).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[CH2:35]([CH:42]1[CH2:47][CH2:46][N:45]([C:48]2[C:53]([Br:54])=[CH:52][N:51]=[C:50]([NH2:55])[C:49]=2[N+:56]([O-])=O)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[CH2:35]([CH:42]1[CH2:47][CH2:46][N:45]([C:48]2[C:53]([Br:54])=[CH:52][N:51]=[C:50]3[NH:55][C:67]([C:69]4[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=4)=[N:56][C:49]=23)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCC(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Cc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 22.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 4-(4-benzylpiperidin-1-yl)-5-bromo-3-nitropyridin-2-amine (100 mg, 0.25 mmol), DMF (0.20 mL), ethanol (1.25 mL), 1M Na2S2O4 (3 eq, 0.75 mmol, 0.75 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.28 mmol, 66 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (32 mg, 22%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 1.44-1.49 (m, 2H, 2× piperidine CHAHB), 1.73 (app d, J=11.0 Hz, 2H, 2× piperidine CHAHB), 1.78-1.85 (m, 1H, piperidine CH), 2.61 (app d, J=7.1 Hz, 2H, PhCH2), 3.31-3.34 (m, 2H, 2× piperidine NCHAHA), 3.85 (app d, J=11.9 Hz, 2H, 2× piperidine NCHAHA), 4.19 (d, J=7.9 Hz, 2H, CH2—NHBOC), 7.20 (t, J=7.3 Hz, 1H, phenyl H-4), 7.23 (d, J=7.0 Hz, 2H, phenyl H-2 & H-6), 7.31 (t, br, J=7.4 Hz, 2H, phenyl H-3 & H-5), 7.38 (d, J=8.2 Hz, 2H, phenyl H-3′ & H-5′), 7.43 (t, br, J=5.9 Hz, 1H, CH2—NHBOC), 8.11 (d, J=8.9 Hz, 2H, phenyl H-2′ & H-6′), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.03 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CN
Solvent: CO
Product: CNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 250 mg of 4-hydroxyphenethyl bromide in a round-bottomed flask, a 10 M excess of MeNH2 (6.2 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After filtration, the solvent was removed to give a brown oil in 80% yield. TLC (EtAc:MeOH, 9:1 v/v): RF=0.33. 1H NMR, δ: 9.42 (s, 1H), 7.10 (d, 2H), 6.75 (d, 2H), 3.60 (s, 3H), 2.84 (t, 2H), 2.60 (t, 2H), 1.90 (s, 1H). 13C NMR, δ: 167.5, 131.2, 128.3, 112.4, 41.5, 36.4, 35.0. Anal. calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26%. Found; C, 71.50; H, 8.80; N, 9.20%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:29])[C@@H:19]2[C@H:22]([O:24][Si](C)(C)C)[CH3:23])[C:16]=1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])\[CH3:14])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:29])[C@@H:19]2[C@H:22]([OH:24])[CH3:23])[C:16]=1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])\[CH3:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2 S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-trimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate obtained in Example 7-(1) in ethyl acetate (73 ml) were added acetic acid (12.5 ml) and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (51.1 ml) at 0° C. After stirring at 0° C. for 30 minutes, the reaction mixture was taken up into a mixture of ethyl acetate (300 ml) and water (175 ml). The organic layer was separated, washed in turn with water, brine, aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (315 ml) eluting with a mixture of n-hexane and ethyl acetate (9 1-2:5 V/V) to give allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (20.40 g).