Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12][CH2:13]OS(C)(=O)=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:7]=2)[CH:3]=1.[Li+].[B-](CC)(CC)CC>C1COCC1.CCOCC.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12][CH3:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:46])[CH3:47])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CCOS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-(methylsulfonyloxy)propoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (28.5 mg, 0.039 mmol) in THF (1 ml) at 0° C. was added Superhydride (0.059 ml, 0.059 mmol). It was stirred at R.T. over three hours, LC/MS showed no reaction. Another 1.5 eq of super hydride was added and it was stirred at R.T. overnight. LC/MS showed partial convertion to product, another 1.5eq of superhydride was added and it was stirred at R.T. overweekend. LC/MS showed the reaction was complete. The reaction was cooled to 0° C. and diluted with ether, water was added and layer separated, the organics were washed with brine and dried over magnesium sulfate, filtered and concentrated. It was purified by Biotage LC eluting with 25% EtOAc/Hex to afford title compound (15 mg, 0.024 mmol, 60.5% yield) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.31 (m, 2H), 7.03 (t, J=8.9 Hz, 2H), 6.68 (s, 1H), 5.66 (AB, Δν=17.4 Hz, J=10.7 Hz, 2H), 4.77 (m, 1H), 3.72 (m, 2H), 3.59 (t, J=8.2 Hz, 2H), 3.34 (AB, Δν=23.5 Hz, J=8.8 Hz, 2H), 3.09 (m, 2H), 2.40 (m, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.84 (m, 2H), 1.70 (m, 1H), 1.44 (s, 9H), 0.91 (m, 2H), 0.84 (t, J=7.3 Hz, 3H), −0.06 (s, 9H). LC/MS (HPLC method 4): tR=4.99 min, 632.2(MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[CH2:29][S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29](=[CH:36][CH:33]4[CH2:35][CH2:34]4)[S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Solvent: CO
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)SC(=CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
Into a 50-mL scaled tube, was placed a solution of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione (100 mg, 0.22 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (47 mg, 0.67 mmol, 2.99 equiv), piperidine (9.5 mg, 0.11 mmol, 0.50 equiv), dichloromethane (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 28 mg (24%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-5-(cyclopropylmethylidene)-1,3-thiazolidine-2,4-dione as a white solid. LC-MS (ES, m/z): 499 (M+H)+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[C:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:33](=[O:41])(=[O:40])[NH:32][N:31]=1.Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CC#N.O.C(Cl)Cl>[C:47]([O:46][C:44](=[O:45])[CH2:43][N:25]1[C:26]2[C:22](=[CH:21][C:20]([F:19])=[CH:28][CH:27]=2)[C:23]([C:30]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[S:33](=[O:40])(=[O:41])[N:32]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[N:31]=2)=[C:24]1[CH3:29])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1c(C2=NN(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzyl bromide (10 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 mL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>CO.C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:18][CH3:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-benzyl-4,5-dichloro-2H-pyridazine-3-one (22.31 g, 87.47 mmol), prepared as described in Example 244A, in dry MeOH (175 mL) at 0° C., was added dropwise a solution of sodium methoxide in methanol (25% weight in MeOH, 25 mL). The mixture was slowly warmed up to room temperature and stirred for 18 h. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. The filtrate was concentrated to afford the title compound, 2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one (22.2 g) which was >95% pure as judged by HPLC and was used in the next reaction, Example 354B, without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:46](=[CH:47][CH:48]=1)[CH2:45][C@:27]1([C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]1=[O:44])[CH2:26]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:22][C:23]3[CH:24]=[C:25]4[C:46](=[CH:47][CH:48]=3)[CH2:45][C@:27]3([C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:28]3=[O:44])[CH2:26]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (21 mg, 0.07 mmol, described in Intermediate 49), (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (26 mg, 0.07 mmol, described in Intermediate 9, step B), HOBT (15 mg, 0.10 mmol), and EDC (19 mg, 0.10 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=661 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6](O)[CH3:7])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([N:11]=[N+:12]=[N-:13])[CH3:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)c1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](N=[N+]=[N-])c1ccc(F)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a cooled solution (−15° C.) of the product of Step 1 (23.5 g, 0.168 mol) in toluene (300 ml) was added diphenylphosporyl azide (55.4 g, 0.395 mol) followed by DBU (30.4 ml, 0.2 mol). After stirring overnight, the resulting biphasic solution was poured into 500 ml 1 N HCl. The aqueous layer was extracted with toluene and the combined organic layers were washed with water, 1 N HCl and dried over Na2SO4. After removal of solvent, 25 g of crude product was obtained and was carried on to next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)[CH:44]=1)[C:39](O)=[O:40])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C=O)C>[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:44]=1)[C:39]([NH:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1)=[O:40])([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:26])[CH3:27]
Reactant: Nc1nccs1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2nccs2)c1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
HATU (513 mg, 1.35 mmol) was added to 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]benzoic acid (520 mg, 1.08 mmol) followed by addition of DMF (5 mL), disopropylethylamine (0.48 mL) and 2-aminothiazole (135 mg, 1.35 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:2 to 2:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (425 mg, 70%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH2:26]>CC(O)C>[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH:26][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: NC[C@H](O)CO
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Product: COc1ccc2nc(NC[C@H](O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 12 h

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][C@@H:11]([CH3:12])[C:3]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C@H:11]([CH3:12])[CH2:10]1)(=[O:15])[CH3:14]
Reactant: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Yield: 70 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45 g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2 hours. After cooling, excess solvent was removed under vacuum. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (3:1) to give (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.25 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03 (m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d, J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS (APCI+) [M+H] +227.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([NH:16][C:17]([C:19]2[CH:39]=[CH:38][C:22]3[N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>CN(C)C=O>[C:1]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([NH:16][C:17]([C:19]2[CH:39]=[CH:38][C:22]3[N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34](=[NH:35])[NH:36][C:47](=[O:54])[C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[CH:32][CH:33]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(CCc2ccc(C(=N)NC(=O)c3ccccc3)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21
Temperature: 0 °C

Procedure:
1.0 g (2 mmol) of 2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid-(4-benzamido-piperidinyl)-amide and 3.2 ml Triethylamine (23 mmol) are dissolved in 10 ml of dimethyl formamide. The mixture is cooled down to 0° C. and 0.418 ml of benzoyl chloride (3.6 mmol) are slowly added dropwise. After 2 hours 20 ml of water are added to the mixture, and the aqueous phase is extracted with 20 ml of acetic ester. The organic phase is again washed with waterand dried over sodium sulphate. The solvent is distilled off under vacuum. The residue is chromatographed over silica gel with acetic ester, and the oily product is triturated with petroleum ether. The precipate is filtered and washed with petroleum ether. Yield: 0.160 g (15%); MPt: 150-154° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:4]([OH:5])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].BrCCl.O>CN(C)C=O.CCOCC>[CH3:1][C:2]1[C:3]2[O:10][CH2:11][O:5][C:4]=2[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)c(O)c1O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1OCO2
Temperature: 100 °C
Yield: 62 %

Procedure:
To a stirred solution of 2.97 g of 3,6-dimethylcatechol and 3.86 g of potassium carbonate in 60 mL of N,N-dimethylformamide is added 1.69 mL of bromochloromethane. A reflux condenser is attached and the mixture heated in an oil bath to 100° C. for 24 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of water and 200 mL of ether. The aqueous layer is separated and extracted with ether. The combined ether layers are dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.0 g of 4,7-dimethyl-1,3-benzodioxole as a light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.C[O-:19].[Na+].[CH:21]([C:23]([CH3:25])=O)=[CH2:22]>CO>[NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[C:6]([CH2:22][CH2:21][CH2:23][CH3:25])([CH2:13][CH2:14][C:15](=[O:19])[CH3:16])[CH2:5]2
Reactant: C=CC(C)=O
Reactant: CCCCC1Cc2c(cc(F)c(N)c2Cl)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCC1(CCC(C)=O)Cc2c(cc(F)c(N)c2Cl)C1=O
Temperature: 45 °C

Procedure:
A solution of 5-amino-2-butyl-4-chloro-6-fluoro-1-indanone (2.705 g, 10.6 mmol) in methanol (17 mL) was treated with sodium methoxide (0.5M solution in MeOH, 4.2 mL, 2.1 mmol) and methyl vinyl ketone (1.3 mL, 15.75 mmol). The resulting solution was stirred under a nitrogen atmosphere and heated in an oil bath at 45° C. for 21 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel and the filtrate was evaporated under vacuum to afford crude 5-amino-2-butyl-4-chloro-6-fluoro-2-(3-oxobutyl)-1-indanone.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[C:10]([C:18]2([OH:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:18]2([OH:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2(O)CCOCC2)nc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(O)CCOCC2)nc1Cc1ccccc1
Yield: 73.8 %

Procedure:
A mixed solution of 377 mg of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-methoxymethyloxypyridine, 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was stirred at room temperature overnight. The reaction solution was neutralized by an aqueous sodium bicarbonate solution, and ethyl acetate was added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 60% ethyl acetate/hexane, to give 241 mg of the target compound.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:11])[CH2:9][CH3:10].F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>C(OCC)(=O)C>[CH3:7][C@H:8]([O:11][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH2:9][CH3:10]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CC[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Sodium tert-butoxide (3.24 g, 33.7 mmol) was added portionwise with stirring to (2S)-2-butanol (10 g, 135 mmol). 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added to the resulting suspension and the mixture heated to 50° C. for 6 hours when LCMS showed complete reaction. After cooling the mixture was diluted with ethyl acetate (100 ml), and washed with water (50 ml) and the aqueous layer extracted again with ethyl acetate (50 ml). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated in vacuo (at 62° C. to remove the excess alcohol). The residue (2.52 g) was dissolved in dichloromethane and purified on an aminopropyl cartridge (110 g) using a Flashmaster II apparatus and eluting with a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.935 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41]>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH:30][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.3 %

Procedure:
A solution of 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethylamine (71 mg, 0.168 mmol) in CH2Cl2 (5 mL) at −78° C. was treated with 2,6-lutidine (33 μL, 0.284 mmol), Tf2O (45 μL, 0.948 mmol) and warmed slowly to ambient temperature. After 17 h, the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative-chromatography over silica gel (eluted in hexanes/EtOAc 1:1) to afford the title compound (29 mg, 30%): 1H NMR (CDCl3 400 MHz) δ 7.61 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 6.44 (m, 1H), 5.22 (dd, J=11.7, 2.9 Hz, 1H), 4.12 (d, J=11.7 Hz, 1H), 3.57 (m, 3H), 3.01 (m, 1H), 2.56 (m, 1H), 2.33 (m, 1H), 1.91 (m, 2H), 1.56 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[C:9]1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-benzyl-3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (2.59 g, 6.35 mmol) in dry THF (15 mL) was added a solution of NaOH (3.9 g, 98 mmol) in H2O (15 mL). The reaction mixture was stirred overnight at 80° C. An additional portion of NaOH (4.25 g, 106 mmol) was added and the reaction mixture was stirred at 100° C. during 7 h. The organic solvent was evaporated and the residue was acidified with aqueous 5 M HCl (55 mL). The product was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (3×20 mL) and dried (Na2SO4). The remaining oil was triturated with heptane (20 mL). The off-white solids were filtered off to give 1.29 g (51%) ACI-06.