Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.[CH:20]([C:22]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26]([NH2:28])=[O:27])=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCCP(=O)=O>C(N(CC)CC)C>[NH2:28][C:26]([CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:22]=1[C:20]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]2[C:10]=1[NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:27]
Reactant: COc1cccc(OCC(N)=O)c1C=O
Reactant: Cc1cccc(C)c1NC=O
Reactant: Nc1ccc(F)cn1
Agent: CCCP(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: COc1cccc(OCC(N)=O)c1-c1nc2ccc(F)cn2c1Nc1c(C)cccc1C
Temperature: 100 °C
Reaction time: 7 h

Procedure:
4.2 0.149 g of 12, 0.112 g of 2-amino-5-fluoropyridine 4, 0.209 g of 2-(2-formyl-3-methoxyphenoxy)acetamide 3, 0.286 ml of triethylamine and, dropwise, 2.5 ml of T3P® [=propylphosphonic anhydride (50% solution in ethyl acetate)] are introduced successively into a flask with ice-cooling and under an inert gas. The reaction mixture is stirred at 100° C. for 7 h. The mixture is subsequently subjected to conventional work-up, giving 0.2 g (40%) of “A1”.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:25]
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-4,5-dichloro-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH2:19]([SH:24])[CH2:20][CH2:21][CH2:22][SH:23].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[SH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:24][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: SCCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C(=O)c1ccc(SCCCCS)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
40 g (0.15 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one and 109 g (0.89 mol) of 1,4-butanedithiol are dissolved in 300 ml of dimethylacetamide, and the solution is stirred at around 100° C. together with 41 g of potassium carbonate for 5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate -hexane (20:80) as an eluent. Melting point 98 ° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.36 (t, 1H), 1.76-1.90 (m, 4H), 2.53-2.62 (m, 6H), 2.98-3.04 (m, 2H), 3.69 (t, 4H), 7.25 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]([F:71])([F:70])[C:61]1[CH:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[CH:66][C:61]([C:60]([F:71])([F:70])[F:59])=[CH:62][CH:63]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(C(F)(F)F)cc2)=C3c2cc(F)cc(F)c2)CC1
Yield: 69 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (69%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31].C(Cl)(Cl)Cl.ClCCl>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][CH:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.50 g, 3.56 mmol) was treated with a solution of 7 M ammonia in methanol (30 mL) at 140° C. for 15 hours according to the method described in Part F of Example 1. Chloroform was used in the work-up procedure instead of dichloromethane. The crude product was purified by flash chromatography (silica gel, elution with 97:3 dichloromethane/methanol) to afford 2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.17 g) as a yellow solid. Recrystallization afforded white needles, mp 235-237° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[Cl-].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH2+:26][CH2:25][CH2:24]2.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([CH2:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:25][CH2:24]2
Reactant: Clc1ccc2c(c1)CC[NH2+]C2
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(CN2CCc3cc(Cl)ccc3C2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
Ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (300 mg, 1.22 mmol) and 6-chloro-1,2,3,4-tetrahydroisoquinolinium chloride (267 mg, 1.59 mmol) were dissolved in 6.2 mL of dichloroethane, and the reaction was neutralized by adding triethylamine dropwise to reach pH 7. The reaction mixture was re-acidified by adding glacial acetic acid (420 μl, 7.34 mmol). MP-Cyanoborohydride resin (1 spatula tip, excess) was added, and the reaction was stirred and heated at 120° C. for 20 minutes in a Emrys Optimizer™ microwave. The crude reaction mixture was filtered with methanol, concentrated in vacuo and redissolved in dimethylsulfoxide, then was purified by reverse phase HPLC, eluting with 20-90% acetonitrile in water to afford ethyl 1-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 397.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:35][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CCCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 9.96 g (0.088 mol) of cycloheptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -12° C. and -15° C. during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 20.4 g (85.2%) of the named compound as yellow crystals, m.p.: 172°-174° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>ClC(Cl)C.O1CCCC1.ClCCl.O1CCCC1>[Cl:7][C:8]1[C:9]([C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(CO)NC(=O)c1cccnc1Cl

Procedure:
134 ml (1.4 mole) of 2-amino 2-methyl propanol are dissolved in 600 ml of a dichloroethane/tetrahydrofuran mixture (85/15 v/v) and the solution is cooled in an ice/sodium chloride bath. 70.4 g (0.4 mole) of 2-chloro nicotinic acid chloride, prepared as described in Example 1 and dissolved in 770 ml of a dichloromethane/tetrahydrofuran mixture (85/15 v/v) are added such that the temperature is maintained at or below 0° C.
Reaction SMILES: BrC1C=C(C[N:11]([CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[O:13])C=CC=1C#N.[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].[C:55]([O-:58])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:12][C:14]4[CH:15]=[C:16]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([CH:44]=[O:45])[CH:47]=5)[CH:17]=[CH:18][C:19]=4[O:58][CH3:55])=[O:21])[CH:15]=3)=[O:13])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C([O-])[O-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C#N)c(Br)c1)C(=O)c1cccc(C(N)=O)c1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Yield: 108.2 %

Procedure:
A mixture of N-[(3-bromo-4-cyanophenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.779 g, 0.00120 mol) in dioxane (9 mL) with (3-formylphenyl)boronic acid (234.7 mg, 0.001565 mol) was treated with a solution of Na2CO3 (382.8 mg, 0.00361 mol) in H2O (3 mL). The mixture was purged with N2 for 10 min, then Tetrakistriphenylphosphine palladium (0) (69 mg, 0.00060 mol) was added. The mixture was microwaved at 150° C. for 30 min. The reaction was quenched with H2O, then the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with H2O, then sat. aq. NaCl, dried (Na2SO4) and concentrated giving a residue which was purified on a Chomatotrom™ Plate (2000μ) silica gel [DCM-MeOH, 0-6%] to afford the title compound (438 mg). However, there was loss of Br during the reaction and the des-bromo compound did not separate under the chromatographic conditions and the product 70% pure, with effectively 306 mg (38%) desired product obtained. LC-MS m/z 675.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](=[O:22])(=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:23]Br>C(Cl)(Cl)(Cl)Cl.[W]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](=[O:22])(=[O:21])[NH:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH2:8][Br:23]
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Yield: 81.8 %

Procedure:
A solution of 1.08 g (3.36 mmol) of 3-fluoro-4-methyl-2'-(N-t-butylsulfamoyl)biphenyl (from Step A) in 20 mL of CCl4 was stirred at reflux under irradiation from a 100-watt tungsten lamp as a solution of 3.5 mmol of bromine in approximately 13 mL of CCl4 was added dropwise over 1.5 hour. After being stirred at reflux overnight, the solution was cooled and concentrated. The residue was crystallized from EtOAc-hexane to give 1.10 g of the title compound as an off-white solid, mp 138°-140° C. (estimated purity 87%; contained minor unbrominated and dibrominated contaminants by TLC); mass spectrum (FAB) m/e 400, 402 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH3:30])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and iodoethane.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:55]=[CH:54][C:50]([C:51]([OH:53])=[O:52])=[C:49]([Cl:56])[CH:48]=1)(O)O.B(O)O>>[C:51]([C:50]1[CH:54]=[CH:55][C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:48][C:49]=1[Cl:56])([OH:53])=[O:52]
Reactant: O=C(O)c1ccc(B(O)O)cc1Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(Cl)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-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]chrysene-3a-carboxylic acid (example 4a) using 4-borono-2-chlorobenzoic acid as the reactant boronic acid. Purification of the product was accomplished by first using Biotage flash chromatography with a 0-50% ethyl acetate in hexanes gradient with 0.1% acetic acid added to the mixture. The compound was not sufficiently pure, so further purification by prep HPLC followed (acetonitrile/water mobile phase with TFA buffer on a C18 reverse phase column). After concentrating the desired fractions, the title compound was isolated as a white film (6.1 mg, 6.8% yield over two steps). LCMS: m/e 591.60 (M−H)−, 1.54 min (method 1). 1H NMR (500 MHz, Pyr) δ ppm 0.92 (br. s., 6H), 0.96 (s, 3H), 1.10 (s, 3H), 1.11 (s, 3H), 1.18-1.84 (m, 15H), 1.83 (s, 3H), 1.89 (t, J=13.28 Hz, 1H), 1.99 (br. s., 1H), 2.09 (dd, J=17.09, 6.10 Hz, 1H), 2.24-2.33 (m, 2H), 2.66 (d, J=12.51 Hz, 1H), 2.81 (t, J=11.75 Hz, 1H), 3.54-3.63 (m, 1H), 4.82 (s, 1H), 5.00 (s, 1H), 5.37 (d, J=5.80 Hz, 1H), 7.24 (d, J=8.24 Hz, 1H), 7.51 (s, 1H), 8.21 (d, J=7.63 Hz, 1H).
Reaction SMILES: [CH:1]([S:3](N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1)(=[O:5])=[O:4])=[CH2:2].Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>C(Cl)Cl>[CH:1]([S:3]([N:36]1[CH2:37][C:34]([F:38])([F:33])[CH2:35]1)(=[O:5])=[O:4])=[CH2:2]
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared by a similar procedure to 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using 3,3-difluoroazetidine hydrochloride salt. 1-Ethenesulfonyl-3,3-difluoro-azetidine was isolated as a light brown oil after flash chromatography (SiO2, DCM) (171 mg, 61%). 1H NMR δ (ppm) (CDCl3): 6.56 (1 H, dd, J=16.56, 9.83 Hz), 6.40 (1 H, d, J=16.59 Hz), 6.20 (1 H, d, J=9.83 Hz), 4.32-4.17 (4 H, m)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:13][C:12](=[O:14])[CH2:11][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([OH:15])=[C:2]([Cl:1])[C:10]=2[O:9][CH:8]=1
Reactant: O=C(O)Cc1coc2c(Cl)c(O)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2c(Cl)c(O)ccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of (7-chloro-6-hydroxy-1-benzofuran-3-yl)acetic acid (1.65 g) and MeOH (40 mL) was added conc. H2SO4 (0.078 mL). The mixture was stirred at 60° C. for 3 h. The mixture was concentrated in vacuo. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in toluene and hexane. The insoluble material was filtered and washed with toluene and hexane. The filtrate was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[O:14][C:13]3[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][S:10][C:9]=2[CH:20]=1)=[O:4].[N+:22]([O-])([OH:24])=[O:23].S(=O)(=O)(O)[OH:27]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[O:14][C:13]3[C:15]([Cl:19])=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[CH:18][C:12]=3[CH2:11][S:10](=[O:27])[C:9]=2[CH:20]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)SCc1cccc(Cl)c1O2
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1O2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Compound of Example 15b (4.1 g, 12.8 mmol) was added to solution of nitrating mixture (nitric acid 200 mL and sulfuric acid 20 mL) at 0° C. and stirred for 18 h. The reaction mixture was poured slowly with stirring into ice water (200 mL). The solid separated was filtered, washed with water and dried to obtain the title compound. Yield: 2.5 g, (52%); 1H NMR (CDCl3, 300 MHz): δ 2.65 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.57 (s, 2H, CH2), 8.16 (d, 2H, Ar), 8.35 (d, 2H, Ar); MS: m/e (ES−) 380 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CNC.[CH3:39][OH:40]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([O:40][CH3:39])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: CO
Agent: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(OC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropyl ethyl amine (0.05 g, 0.407 mmol) and 1M dimethyl amine in methanol (0.061 g, 1.36 mmol). The reaction mixture was heated at 50° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue obtained was purified by column chromatography to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one (0.005 g, 10%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].N1C=CC=CC=1.[S:14](Cl)(Cl)=[O:15]>C(Cl)Cl>[O:15]=[S@:14]1[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7]1
Reactant: OC[C@H]1CCCN1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[S@@]1OCC2CCCN21
Temperature: 25 °C
Yield: 100 %

Procedure:
(R)-2-Pyrrolidinemethanol (1.00 g; 9.88 mmol), prepared according to Example 1, and 6 mL methylene chloride were added to a 50 mL, 3-neck round-bottom flask equipped with a reflux condenser topped with a CaCl2 drying tube, an addition funnel and a magnetic stirrer. Pyridine (1.63 mL; 20.16 mmol) was added, and the solution stirred in a room temperature water bath. Thionyl chloride (1.20 g; 10.08 mmol) in 4 mL methylene chloride was added over 15 minutes and washed in with 1 mL methylene chloride. After stirring for 45 minutes at ambient temperature, the reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature and stirred for an additional 2 hours. Hexanes (11 mL) was added and the mixture was stirred in a 0°-5° C. ice bath for 1 hour. After filtration to remove precipitated pyridine hydrochloride, the solvent was removed on a rotary evaporator with a 40° C. water bath to yield 1.47 g (9.88 mmol) of (R)-1-oxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine as a brown oil.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Reactant: [N-]=C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2Cl2 (20 mL) was added oxalylchloride (1.30 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of NaN3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm-1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J =8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1 =J2 =8.1 Hz, J3 =6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ0.4, 112.6 (d, JCF =26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF =241 Hz)