Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH:6]([O:69][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:77])[CH3:2].[N-:78]=[N+:79]=[N-:80].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:78]=[N+:79]=[N-:80])[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH:6]([OH:69])[CH2:5][C:4]1=[O:77])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 34.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (68 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (20 mg) and the mixture heated to 70° C. After 4 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (17.5 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: C[C@@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: C[C@@H]1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 26 (300 mg; 1.04 mmol; 1 eq.), and Intermediate 1 (183.98 mg; 1.04 mmol; 1 eq.). After evaporation of the solvents, the solid residue was triturated with ACN, filtered and dried under vacuum to give the title compound as an off-white solid. 1H NMR (DMSO-d5) δ 12.78 (br m, 1H), 8.50-8.26 (m, 2H), 8.04-7.68 (m, 3H), 3.16 (m, 1H), 3.02-2.90 (m, 1H), 2.69-2.55 (m, 1H), 1.87-1.20 (m, 6H), 0.78 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 5.03 min (Purity: 98.4%). LC/MS (Method B): 426.3 (M+H)−; 428.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[OH:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:2]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(N[C@@H](CO)CC(=O)N1CCOCC1)OCc1ccccc1
Yield: 32.4 %

Procedure:
A solution of EXAMPLE 21B (13.5 g, 57.4 mmol) and morpholine (10.0 mL, 115 mmol) in dioxane (100 mL) was stirred at 70° C. for 18 hours. The solution was concentrated and purified by silica gel chromatography eluting with 10% methanol/ethyl acetate to provide the desired product 6.0 g, 86%).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][O:12][S:25]([CH3:24])(=[O:27])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Step A To the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol (1.1 g, 5 mmol) prepared in Example 116a Step B. and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) at 0° C. was added a dichlormethane solution (10 mL) of methanesulfonyl chloride (Aldrich) (0.46 mL, 6 mmol). The reaction mixture was stirred at 0° C. for 1 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester as a yellow oil (1.48 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:49]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:50][CH2:51][NH2:52])[CH2:46][CH2:47][CH3:48]>C(Cl)(Cl)Cl.O>[CH2:45]([N:49]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:50][CH2:51][NH:52][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:43])[CH2:46][CH2:47][CH3:48]
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: CCCCN(CCN)CCCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (76 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (66 mg, yield 42%).
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C([N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[CH:52]=O)(OCC1C=CC=CC=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:56])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:56])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:52][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51][NH:46]2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC1CCCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(CC2CCCCN2)C[C@@H]1CCCB(O)O
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and cbz-piperidine-2-carboxaldehyde (173 mg, 0.7 mmol), stirred for 3 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (156 mg, 74%) as a pale amber solid. NMR (D2O) 3.85-4.05 (m, 2 H), 3.76 (d, J=12.5 Hz, 1 H), 3.50-3.65 (m, 3 H), 3.39 (m, 2 H), 2.95 (dt, J1=12.5 Hz, J2=3 Hz, 1 H), 2.55-2.70 (m, 1 H), 2.00 (m, 1 H), 1.80 (m, 2 H), 1.45-1.65 (m, 4 H), 1.15-1.35 (m, 3 H), 0.65-0.72 (m, 2 H). MS (m+1): 314.1; MS (m−H2O+1): 296.2.
Reaction SMILES: C([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10][C:11](=O)[CH3:12])(=O)C>C1(C)C=CC=CC=1>[CH3:12][C:11]1[S:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1ccsc1SC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2ccsc2s1
Temperature: 205 °C
Yield: 91.4 %

Procedure:
A solution of 660 mg (3.1 mmol) of N-acetyl-2-(acetylthio)-3-thiophenamine in 8 ml of toluene was degased in a pyrex tube under high vacuum. The tube was subsequently sealed under high vacuum and heated at 205° C. for 5 hr. Chromatographic separation on silica gel using hexane/EtOAc=5:1 gave 440 mg (80%) of product. 1H NMR (CDCl3) 7.40(s, 2H), 2.82(s, 3H)
Reaction SMILES: C(OC([N:8](C1C=CC=CC=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl.C(O[CH2:39][CH3:40])(=O)C.Cl>C(OCC)(=O)C>[NH2:8][CH:9]([C:40]1[CH:39]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCCCCCCCCCN1CCN(C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCCCCCCCCCN1CCN(C(=O)C(N)c2ccccc2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
2.9 g (6.32 mmole) quantity of 1-(N-t-butoxycarbonylphenylglycyl)-4-decylpiperazine was dissolved in 5 ml of ethyl acetate, and 20 ml of 4N hydrochloric acid-ethyl acetate solution was added thereto with ice-cooling and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a small quantity of ether and dried under reduced pressure, giving 2.5 g (yield: 90 %) of 1-(2-amino-2-phenylacetyl)-4-decylpiperazine as a hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:42][O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=O)[O:55]C2C=CC([N+]([O-])=O)=CC=2)=[CH:49][CH:48]=1.CCN(CC)CC>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:54]([NH:53][C:50]5[CH:49]=[CH:48][C:47]([O:46][CH2:45][CH2:44][O:43][CH3:42])=[CH:52][CH:51]=5)=[O:55])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Reactant: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
A mixture of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 4, step 2, 0.158 g, 0.277 mmol) and 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.118 g, 0.354 mmol) in DCM (3 mL) was stirred at rt for 3 days. Et3N (0.20 mL) was added followed by 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.142 g, 0.428 mmol). The reaction mixture was stirred at rt for 2 h. The yellow solid was collected and washed with DCM to give 0.176 g of crude 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea, which was taken into the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.O.[C:23](OC(=O)C)(=O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][C:23]([CH3:24])=[N:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Solvent: O
Product: Cc1nc2nc(-c3ccncc3)c(-c3cccc(F)c3)nc2[nH]1
Temperature: 140 °C
Yield: 52 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 300 mg, 1.07 mmol) in acetic anhydride (3 mL) was stirred and heated at 140° C. for 4 h. Then polyphosphoric acid was added (0.32 g) and allowed to react at the same temperature for 2 h. Upon cooling, water was added and the product extracted with ethyl acetate. The crude obtained was purified by silica column chromatography eluting with a gradient from CH2Cl2 to CH2Cl2/MeOH 95:5 to afford the title compound as a yellow solid (36 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCCC1.O>Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][N:15]=[N:16][N:17]=2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reaction time: 24 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1 mmol) and lithium hydroxide (1.1 mmol) in 1/1 tetrahydrofuran/water (5 mL). After 24 hours, dilute the reaction mixture with a 0.5M aqueous hydrochloric acid solution and dichloromethane. Separate the layers and extract the aqueous layer three times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid.
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:31][C@H:11]1[C:12]2[C:17]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4M HCl/dioxane (11.2 ml, 44.9 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.600 g, 1.79 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature under nitrogen overnight (20 hours). The mixture was concentrated to dryness and dried on high vacuum line. The crude was suspended in ether, sonicated, and stirred for 5 minutes. The solids were isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether, dried under nitrogen pressure, and dried further on a hi vacuum line to give (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.440 g, 79.8% yield) as a yellow powder. LC/MS (APCI+) m/z 235. The (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride was prepared using an analogous method.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][C@H:11]1[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH3:36].[Cl-].[Li+].Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:35][CH3:36])[CH2:13][CH2:12][C@H:11]1[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2CC[C@@H](OC3CCCCO3)[C@@H]2COCc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
In a flow of argon, to a solution cooled to -78° C., of 13.6 g of (1R,2S,3S)-2-benzyloxymethyl-1-(2-tetrahydropyranyloxy)-3-[2-(p-toluenesulphonyloxy)ethyl]cyclopentane (prepared in Reference Example 5) in 30 ml of dry tetrahydrofuran, 12.5 ml of a 3M solution of ethyl magnesium bromide in diethyl ether was added over a period of 10 min; to the solution, 5 ml of a solution of 8.4 g of lithium chloride and 13.4 g of cupric chloride in 1 l of tetrahydrofuran was added dropwise over a period of 5 min. The mixture was stirred further for 1.5 hrs at the same temperature, for 2 hrs at 0° C., and for 16 hrs at room temperature. The reaction solution was poured into a mixture of 70 ml of 1N hydrochloric acid, ice and 150 ml of diethyl ether, and the ether layer separated was washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1) as eluent to give 8.63 g of the title compound having the following physical characteristics, in a 89.8% yield.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.Cl.[C:28](Cl)(Cl)=[S:29].C>O>[Na+:1].[Na+:1].[Na+:1].[N:4]([C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]2)=[C:28]=[S:29]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1cc(N=C=S)c2c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 129.8 %

Procedure:
To a solution of 78.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt in 500 ml of water is added 17.0 ml of concentrated hydrochloric acid. The solution is cooled to room temperature and 29 g of thiophosgene is added with vigorous stirring. Stirring is continued for 2.5 hours at room temperature. The mixture is treated with activated charcoal, filtered through diatomaceous earth and evacuated by water pump to remove excess thiophosgene. The filtrate is neutralized with 5N sodium hydroxide and evaporated in vacuo to 250 ml. The solution is allowed to crystallize at room temperature, then in an ice bath. The mixture is filtered and the precipitate is washed with ice water, acetone and ether to give a yellow powder. The power is recrystallized from 110 ml of water by warming, then cooling and seeding. The product is collected after standing and the resulting filtrate is concentrated and recrystallized as above. The products are combined and dried by conventional means to yield 36.9 g of 8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][C:15]([S:19][C:20]([Cl:23])([Cl:22])[F:21])=[C:14]1[CH3:24].ClS([N:29]=[C:30]=O)(=O)=O.CN(C)C=O>C(#N)C.ClCCl>[C:30]([C:16]1[C:15]([S:19][C:20]([Cl:23])([Cl:22])[F:21])=[C:14]([CH3:24])[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[C:17]=1[CH3:18])#[N:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C#N)c(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution containing 0.90 g (2.04 mmoles) of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole prepared above in 8 mL of acetonitrile was added a solution of 0.18 mL (0.29 g, 2.07 mmoles) of chlorosulfonyl isocyanate in 1 mL of acetonitrile dropwise over a 5 minute period. After stirring at 0° C. for 2 hours, a solution of 0.18 mL of dimethylformamide in 1 mL of acetonitrile was added and the reaction mixture was maintained at 0° C. for an additional 1.5 hours. The reaction mixture was then diluted with dichloromethane, washed with water and the organic phase was dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure and column chromatography of the residue on silica gel with 4:1 v/v hexane-EtOAc provided 0.80 g (84%) of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole (ASE 215) as a pale yellow solid of melting point 138.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:22][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=N[C:13]=2[CH:27]2[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH:29]1[CH2:28][CH:27]([C:13]2[CH:38]=[C:15]3[C:20]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:18]=[N:17][N:16]3[C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(C3CN(C(=O)OC(C)(C)C)C3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2c(C3CNC3)cc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 19e (170 mg, 0.335 mmol) in DCM (2 mL), TFA (2 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated. The resulting residue was dried in vacuo for 4 h and suspended in ether. The mixture was concentrated and the resulting residue was dried in vacuo overnight to obtain ethyl 4-(6-(azetidin-3-yl)-4-morpholinopyrrolo[1,2-b]pyridazin-7-yl)benzoate trifluoro acetic acid salt (19g), which was used without further purification in the next step.