Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C(O[CH2:23][CH3:24])(OCC)(OCC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)(=O)C>[CH3:24][C:23]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=2)[N:27]=[N:26][N:25]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)Cc1ccc(N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(-n2nnnc2C)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(5-aminopyridin-2-yl)acetate (1.314 g, 7.29 mmol) dissolved in acetic acid (24.31 ml) and added triethyl orthoacetate (2.69 ml, 14.58 mmol) and sodium azide (0.881 g, 13.55 mmol). The reaction was stirred at 80° C. for 3 hrs. When LC-MS showed reaction was not complete, added more triethyl orthoacetate (2.69 ml, 14.58 mmol) and sodium azide (0.881 g, 13.55 mmol) then continued heating at 80° C. overnight. Evaporated off acetic acid then diluted with ethyl acetate and washed with saturated NaHCO3 solution, brine, then dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography through an ISCO 40 g Redi-sep column and eluting with 5% MeOH/DCM to yield title compound: LC-MS: M+1=248
Reaction SMILES: [F:1][C:2]1([F:26])[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH:23]1[CH2:25][CH2:24]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[C:40]([O:43][C@H:44]1[CH2:61][CH2:60][C@@:59]2([CH3:62])[C:46](=[CH:47][CH2:48][C@@H:49]3[C@@H:58]2[CH2:57][CH2:56][C@@:54]2([CH3:55])[C@H:50]3[CH2:51][CH2:52][C@@H:53]2[O:63][CH:64]2[CH2:66][CH2:65]2)[C:45]1([F:68])[F:67])(=[O:42])[CH3:41]>O>[CH:7]1([CH2:6][CH2:41][C:40]([O:43][C@H:44]2[CH2:61][CH2:60][C@@:59]3([CH3:62])[C:46](=[CH:47][CH2:48][C@@H:49]4[C@@H:58]3[CH2:57][CH2:56][C@@:54]3([CH3:55])[C@H:50]4[CH2:51][CH2:52][C@@H:53]3[O:63][CH:64]3[CH2:65][CH2:66]3)[C:45]2([F:67])[F:68])=[O:42])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:59]1([CH2:60][CH2:61][C:44]([O:20][C@H:19]2[CH2:18][CH2:17][C@@:16]3([CH3:21])[C:3](=[CH:4][CH2:5][C@@H:6]4[C@@H:15]3[CH2:14][CH2:13][C@@:11]3([CH3:12])[C@H:7]4[CH2:8][CH2:9][C@@H:10]3[O:22][CH:23]3[CH2:24][CH2:25]3)[C:2]2([F:26])[F:1])=[O:43])[CH:46]=[CH:47][CH:48]=[CH:49][CH:58]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC5CC5)[C@@]4(C)CC[C@@H]32)C1(F)F
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC(=O)CCC5CCCC5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC(=O)CCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
4,4-Difluoro-17β-(cyclopropyloxy)androst-5-en-3β-ol is treated with acetic anhydride and pyridine. The mixture is poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated and dried and the solvent is evaporated to leave as a residue, 3β-acetyloxy-4,4-difluoro-17β-(cyclopropyloxy)androst-5-ene. 3β-(Cyclopentanepropionyloxy)-4,4-difluoro-17β-(cyclopropyloxy)androst-5-ene and 3β-(benzenepropionyloxy)-4,4-difluoro-17β-(cyclopropyloxy)androst-5-ene are obtained in a similar way using the appropriate acid chlorides.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 45 °C
Yield: 60.9 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 3.2 mmol) in n-butyl alcohol (12 mL) was added 6-aminoindazole (0.47 g, 3.52 mol) and DIPEA (0.86 mL, 4.80 mmol). After heating at 45° C. for 15 h, the mixture was cooled to room temperature, and the resulting precipitates were collected by filtration to give 2-chloro-N-(1H-indazol-6-yl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1 g).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.[Si](C#N)(C)(C)C.[N:33]1([C:38](N2C=CN=C2)=[O:39])C=CN=[CH:34]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:22]([C:21]4[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=4)[CH2:34][NH:33][C:38]3=[O:39])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: O=C1NCC(c2cccc(Cl)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.293 g, 2.2 mmol), 3-chloro benzaldehyde (0.227 mL, 2 mmol), TMSCN (0.25 mL, 2 mmol), PdC (10%, 0.01 g), TEA (0.613 mL, 4.4 mmol), di-(imidazol-1-yl)methanone (0.389 g, 2.4 mmol) as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1.B(Br)(Br)Br>ClCCl>[OH:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:11]([C:4]4[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=4[OH:2])=[CH:12][NH:13][C:14]3=[N:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3[nH]cc(-c4c(O)cccc4O)c3c2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a suspension of 3-[3-(2,6-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol (23 mg, 0.066 mmol) in dichloromethane (1 mL) at −78° C. was added 1 M boron tribromide solution in dichloromethane (0.23 mL, 0.23 mmol) dropwise. The reaction mixture was warmed up to room temperature over 4 h, then quenched with water and neutralized to pH8 with a saturated solution of aqueous sodium bicarbonate. The mixture was extracted with EtOAc three times and the extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of methanol/dichloromethane afforded 2-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-benzene-1,3-diol as a beige solid (17 mg, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.43 (d, J=8.0 Hz, 1H), 6.73 (dd, J=2.5, 7.5 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 7.00 (t, J=2.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 3.10 (broad s, 2H), 9.49 (broad s, 1H), 11.7 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40][C:41]#[N:42])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40][C:41]#[N:42])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(CC#N)C2c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC#N)C2c1ccc2c(c1)OCO2
Yield: 87.7 %

Procedure:
1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-propoxyindane (240 mg, 0.42 mmol) was stirred in methylene chloride (3 ml) with TFA (0.8 ml) under argon at room temperature for 1 h then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the product as an oil (190 mg, 88%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(O)(C)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
Celite (66 g) was added to a solution of 4-hydroxy-N-CBZ-piperidine (18 g, 76.5 mmol) in methylene chloride (500 ml), followed by pyridinium chlorochromate (33 g, 153 mmol). The mixture was stirred overnight, and then isopropyl alcohol (12 ml) was added over a period of 3 hours. The reaction mixture was filtered through silica gel and the filter cake was repeatedly rinsed with methylene chloride and ethyl acetate. The combined filtrates were evaporated under reduced pressure. Silica gel chromatography using 50% ethyl acetate/hexane, gave 4-oxo-N-CBZ-piperidine as a yellow oil.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]([CH3:16])[S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11]
Reactant: C=CS(=O)(=O)Nc1c(C)cc(C)cc1C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CS(=O)(=O)N(C)c1c(C)cc(C)cc1C
Yield: 100.3 %

Procedure:
22.5 g (0.1 mole) N-mesitylethenesulphonamide, 37.2 g anhydrous sodium carbonate, 52 ml methyl iodide and 1000 ml acetone were mixed and refluxed for 6 hours. The mixture was then filtered and evaporated to dryness. The residue was dissolved in diethyl ether and extracted with 2 N sodium hydroxide solution (to remove remaining starting material). The ether solution was dried over magnesium sulphate and evaporated to dryness. 24.0 g of the crude title compound was obtained as an oil, which solidifies slowly. M.p. c.a. 25° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]([Cl:15])=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[ClH:15].[Cl:15][C:9]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:7]2[C:12]([CH2:13][CH2:14][C@H:5]([CH2:4][NH2:1])[O:6]2)=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NC[C@H]1CCc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: NC[C@H]1CCc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 90.7 %

Procedure:
Treatment of (2R)-2-(azidomethyl)-7-chloro-8-(2-chlorophenyl)chroman (1.5 g, 4.48 mmol) with polymer-bound triphenylphosphine (3 mmol/g, 1.94 g, 5.82 mmol) according to the procedure described for Example 69, Step 10 provided 0.70 g (45%) of ((2R)-7-chloro-8-(2-chlorophenyl)chroman-2-yl)methanamine hydrochloride as a white solid salt, mp 220–222° C.; MS (ESI) m/z 308.1 ([M+H]+); [α]D25=−26.4° (c=1% SOLN, MeOH).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19]O)[N:10]=2)=[CH:4][CH:3]=1.CS([Cl:25])(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:25][CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNc2ccc3c(CCl)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol (example 41, step A, 70 mg, 0.261 mmol) was dissolved in 2 mL tetrahydrofurane and methanesulfonyl chloride (34 mg, 0.297 mmol) and N,N-diisopropyl ethyl amine (41 mg, 0.318 mmol) were added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated off. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). (5-Chloromethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was obtained as a brown solid (59 mg, 79%), MS: m/e=287.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].[O:31]([C:38](Cl)=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=CC=CC=1C(Cl)=O>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:19]2[C:18]1=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:38](=[O:39])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:1]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: COc1ccccc1C(=O)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)Oc1ccccc1)C1c2ccccc2-c2ccccc21

Procedure:
When in the procedure of Example 94 an appropriate amount of the product of Example 77 was substituted for the product of Example 4 and an appropriate amount of phenoxycarbonyl chloride was substituted for 2-methoxybenzoyl chloride and the general procedure of Example 94 was followed the title compound was obtained. Total yield, 0.94 g (82%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-n-propylbenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][C:27]2[S:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[CH:28]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCl>[ClH:1].[S:31]1[C:27]([CH2:26][O:25][CH:23]2[CH2:22][NH:21][CH2:24]2)=[CH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]1=2
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(OCc3cc4ccccc4s3)C2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: c1ccc2sc(COC3CNC3)cc2c1
Reaction time: 2 h
Yield: 213.3 %

Procedure:
1-Chloroethyl chloroformate (322 μL, 1.1 mmol) was added to a solution of 1-benzhydryl-3-(benzo[b]thiophen-2-ylmethoxy)-azetidine (1.04 g, 2.7 mmol) in dichloromethane (17 mL) at room temperature. The reaction mixture was stirred for 2 hours. Methanol (17 mL) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The reaction mixture was then concentrated to dryness and the residue was triturated in petroleum ether (20 mL) to afford the title compound as a yellow solid (600 mg, 90%).
Reaction SMILES: CO.[Cl:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>C(O)(C)C>[Cl-:3].[CH3:9][O:8][Si:7]([CH2:6][CH2:5][CH2:4][N+:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCN(CC)CC
Solvent: CC(C)O
Solvent: CO
Product: CC[N+](CC)(CC)CCC[Si](OC)(OC)OC
Product: [Cl-]
Reaction time: 1 h

Procedure:
A mixture of 60.0 grams of methanol, 60.0 grams of chloropropyltrimethoxysilane and 19.53 grams of triethylamine was prepared. The mixture was heated and allowed to reflux for 96 hours. A pinkish tint was observed. The mixture was vacuum stripped at 80° C. and 29 inches of Hg, for one hour. The mixture became brown in color. Upon cooling, solidified to form a crystal salt. To 8.0 grams of the product was added 2.0 grams of isopropanol wherein the salt dissolved.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Clc1cc(Br)c2ncccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(Cl)cc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g., 0.025 mole] in 50 ml. of tetrahydrofuran was added dropwise over a 10 minute period to a mixture of butyl lithium (2.3 M in hexane, 12.2 ml., 0.028 mole) and 40 ml. of tetrahydrofuran held at -70° C. After an additional 30 minutes at this temperature, a cold (0° C.) solution of diethyl oxalate (14.6 g., 0.10 mole) in 50 ml. of tetrahydrofuran was added dropwise. The reaction mixture was maintained at 0° C. for 1 hour, then quenched at 0°-5° C. with glacial acetic acid (17 ml.) in 50 ml. of tetrahydrofuran. After warming to room temperature the quenched mixture was poured into 500 ml. of water and then diluted with 500 ml. of ethyl acetate and 500 ml. of saturated sodium bicarbonate. The organic layer was separated, washed with 500 ml. of fresh bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated to an oil. Trituration with two 100 ml. portions of hexane gave the title product (2.3 g., m.p. 107°-110° C.; m/e 265/263).
Reaction SMILES: [CH2:1]([C@@](C)(O)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([OH:19])(=[O:18])[C@H:15]([CH3:17])[OH:16].C(N(CC1C=CC=CC=1)C(=NC(C)C)O)(C)C>C1COCC1>[C:14]([O:19][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH:15]([CH3:17])[OH:16]
Reactant: C[C@@](O)(Cc1ccccc1)C(=O)O
Reactant: C[C@H](O)C(=O)O
Agent: CC(C)N=C(O)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: CC(O)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Construction of Benzyl-L-lactic Acid. L-Lactic acid (9 g, 100 mmol) is added to N,N'-diisopropylbenzylisourea (23.3 g, 100 mmol) with stirring. The mixture becomes very viscous within 10 min and is stirred intermittently for 1 h. The volume is then increased to 200 mL with THF, and the mixture stirred for 48 h at room temperature. After cooling the mixture to -15° C., the diisopropylurea is removed by filtration and the THF is evaporated under reduced pressure. The resulting thick oil is pumped under high vacuum for 24 h to give benzyl lactate (17.4 g, 95%) which may be used without further purification.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH:7]([N:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=O)([CH3:9])[CH3:8].[NH2:16][C:17]1[N:22]=[C:21](O)[C:20]([I:24])=[CH:19][N:18]=1>ClCCl>[Cl:4][C:21]1[C:20]([I:24])=[CH:19][N:18]=[C:17]([N:16]=[CH:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH:7]([CH3:9])[CH3:8])[N:22]=1
Reactant: CC(C)N(C=O)C(C)C
Reactant: Nc1ncc(I)c(O)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.5 mL of oxalyl chloride in 35 mL of dichloromethane was added dropwise over 25 minutes to an ice water bath-cooled solution of 7.0 mL of N,N-diisopropylformamide in 65 mL of dichloromethane with magnetic stirring. After a few minutes, 4.74 g of 2-amino-4-hydroxy-5-iodopyrimidine was added in one portion. The bath was removed and the solution was stirred at room temperature for 30 minutes, then refluxed for one and one half hours. The solution was cooled and poured into an equal amount of ice-cold saturated aqueous sodium bicarbonate with stirring. The two phases were partitioned and the organic layer washed with additional bicarbonate(2×), water(1×) and finally saturated aqueous brine. After drying over sodium sulfate and filtration, the solution was evaporated in vacuo to yield 10.13 g of a reddish oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane. Like fractions were pooled, evaporated and triturated with hexanes to give white free flowing crystals, 5.94 g, m.p. 97–100° C.
Reaction SMILES: [N+]([C:4]1N(C)[C:7]([C:10]2N3N=C(N)C=CC3=NN=2)=[N:6][CH:5]=1)([O-])=[O:2].[N+](C1N(C)C(C2N3N=C(N=C[O:40][CH2:41]C)C=CC3=NN=2)=NC=1)([O-])=O.[CH:43]([OH:46])(C)[CH3:44]>O1CCOCC1>[CH:41]([O-:40])([O-:2])[O:46][CH2:43][CH3:44].[CH2:5]([NH:6][CH2:7][CH3:10])[CH3:4]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Reactant: CC(C)O
Solvent: C1COCCO1
Product: CCNCC
Product: CCOC([O-])[O-]

Procedure:
In a manner analogous to that described in Example 13, from 1 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[ 4,3-b]pyridazine and 10 ml. ethyl orthoformate, there was prepared crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[4,3-b]pyridazine which, with 13 ml. of a solvent mixture of isopropanol and dioxan (7:3) and 1.1 ml. diethylamine gave, after a reaction time of 30 minutes at 20° C., subsequent evaporation of the solution in a vacuum at a bath temperature of 80° C., trituration of the residue with a little isopropanol and water and drying for 2 hours at 120° C. in a vaccum, 0.84 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(diethylaminomethyleneamino)-s-triazolo[4,3-b]pyridazine which has a melting point of 155° - 156° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].Cl.O.[CH2:43]1COC[CH2:44]1>C(OCC)C>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]3[S:5][C:4]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)=[N:3][C:2]=3[CH3:1])=[CH:17][CH:16]=2)[C:12]([CH2:43][CH3:44])=[CH:13]1)[CH3:40]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2[nH]ccc2c1
Reactant: C1CCOC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cn1cc(CC)c2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A suspension of 5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole (485 mg, 1.16 mmol), cesium carbonate (1.38 g, 3.49 mmol) and ethyl bromoacetate (0.15 ml, 1.28 mmol) in THF (5 ml) was stirred for 1.5 h at ambient temperature. Diethyl ether and 1N HCl/water 1/1 were added. The ether phase was dried over sodium sulfate and concentrated under reduced pressure to give 635 mg (1.26 mmol, 98%) {3-ethyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.