Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Br:78][C@@H:79]1[C@@H:83]([CH2:84][O:85][C:86](=[O:88])[CH3:87])[O:82][C@@H:81]([N:89]2[C:98]3[N:97]=[CH:96][N:95]=[C:93]([NH2:94])[C:92]=3[N:91]=[CH:90]2)[C@:80]1(C(=O)C)[OH:99].C(=O)([O-])O.[Na+]>O>[C:86]([O:85][CH2:84][C@H:83]1[O:82][C@@H:81]([N:89]2[C:98]3[N:97]=[CH:96][N:95]=[C:93]([NH2:94])[C:92]=3[N:91]=[CH:90]2)[C@H:80]([OH:99])[C@@H:79]1[Br:78])(=[O:88])[CH3:87]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@](O)(C(C)=O)[C@@H]1Br
Agent: O=C([O-])O
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: [Na+]
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
After 50 g of β-cyclodextrin was added to 1 liter of water, the mixture was heated to completely dissolve. The solution was cooled to room temperature and 10 g of 3'-deoxy-3'-bromo-2',5'-O-diacetyladenosine was then added to the solution, and 2.5 g of sodium hydrogencarbonate was added to the mixture over 1 hour. After stirring was continued for further 2 hours, the reaction mixture was extracted 3 times with 500 ml of ethyl acetate. The solvent was distilled off to give 7 g (yield, 78%) of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COC(=O)c1ccc2ccn(Cc3ccc([N+](=O)[O-])cc3)c2c1

Procedure:
1-(4-Nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester was prepared from 1H-indole-6-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 5.75 (s, 2H), 6.66(dd, J=3.1, 0.6 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.60 (t, J=2.8 Hz, 1H), 7.79 (d, J=3.1 Hz, 1H), 8.07 (s, 1H), 8.15 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.28 (d, J=8.7 Hz, 2H); MS (ESI) m/z 311 (MH+); 309 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)CCC>CC#N>[C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:2]3[N:7]=[C:6]([N:10]4[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: NC(=O)C1CCCNC1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CC#N
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCCC(C(N)=O)C4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), nipecotamide (128 mg, 1.00 mmol) and DEA (0.350 mL, 2.01 mmol) in CH3CN (4 mL) was stirred at room temperature for 20 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (4 mL). 2 mL of the nBuOH solution was taken, to which 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (150 mg, 0.68 mmol) was added. The solution was stirred at 116° C. for 6 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (75 mg). MS 442.4 (M+H); UV 208.8, 261.8 nm.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH2:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH2:16][CH3:17]>>[CH2:15]([N:18]([C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1)[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=1)[CH2:16][CH3:17]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: CCCNc1ccc(C(F)(F)F)cc1
Agent: [NH4+]
Product: CCCN(c1ccc(C(F)(F)F)cc1)c1nc(=O)c2cccnc2s1
Yield: 32.5 %

Procedure:
The reaction procedure of Example 57 was followed except that 158 mg of 2-chloronicotinoyl chloride, 68 mg of ammonium thiocyanate and 185 mg of 4-(propylamino)benzotrifluoride were used. As a result, 106 mg of 2-[N-propyl-N-(4-trifluoromethylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(O)C>C(N(CC)CC)C.O>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:19](=[O:20])[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
A mixture of 1.47 g (48 mmol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 0.72 g (9.6 mmol) of 3-amino-1-propanol and 0.024 g (0.24 mmol) of triethylamine was stirred at 100° C. for two hours. Five mL of ethanol was added and the solution was poured into 20 mL of water and allowed to stand 18 hours at 5° C. to crystallize. The product was filtered off, air-dried and recrystallized from 25 mL of ethyl acetate to yield 1.47 g of N-(3-hydroxypropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide, mp 138°-139° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([O:11]COC)(=O)[CH2:6][C:7]([O-:9])=O.[Na].[CH3:16][OH:17]>>[CH3:16][O:17][CH:6]1[C:5](=[O:11])[NH:4][C:2](=[S:3])[NH:1][C:7]1=[O:9]
Reactant: NC(N)=S
Reactant: CO
Reactant: COCOC(=O)CC(=O)[O-]
Agent: [Na]
Product: COC1C(=O)NC(=S)NC1=O

Procedure:
Thiourea (24 g) and methoxymethyl malonate (34 g) was added to a solution of sodium (12 g) in methanol and the mixture heated under reflux for 10 h. The methanol was evaporated under reduced pressure, water (500 ml) added and extracted with ether. The aqueous layer was acidified to pH1 with conc. hydrochloric acid, evaporated to ˜200 ml and the precipitate filtered and dried. Yield 23 g
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].Cl[CH2:42]Cl>>[C:6]([OH:5])(=[O:7])[CH2:42][CH2:36][C:34]([OH:40])=[O:35].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCn3c(=O)[nH]c4ccccc43)c2CC1
Reactant: ClCCl
Product: O=C(O)CCC(=O)O
Product: O=c1[nH]c2ccccc2n1CCCSc1c(Cl)ccc2c1CCNCC2
Yield: 70 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (209 mg, 0.396 mmol) in dichloromethane (10 mL), then add TFA (0.5 mL) dropwise and stir at room temperature overnight. Remove solvents in vacuo then free base using an SCX column, eluting with 7M ammonia in methanol. Concentrate in vacuo, then use a method similar to the General Procedure 2-1 and freeze dry to give the title compound as a solid (140 mg, 70%). MS (ES+) m/z: 388 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N+:13]([O-])=[CH:12][C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[NH4+:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:23])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.20 g, 4.23 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated ammonium hydroxide solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (849 mg, 4.45 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then diluted with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-25% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate gave (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (479 mg) as amber crystals, mp 249.0-250.0° C.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[NH:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[O:1]([CH2:8][C@H:9]1[N:13]([CH2:21][C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]([OH:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: O[C@H]1CN[C@H](COc2ccccc2)C1
Product: O[C@@H]1C[C@@H](COc2ccccc2)N(Cc2ccncc2)C1

Procedure:
The title compound was prepared by a similar method to Preparation 35 from (3R,5S)-5-(phenoxymethyl)pyrrolidine-3-ol [see Preparation 37] and 4-pyridinecarboxaldehyde. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, chloroform:methanol to afford (3R,5S)-5-(phenoxymethyl)-1-(4-pyridinylmethyl)pyrrolidine-3-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl>ClCCl.CO.ClCCl>[F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCNCC1
Reaction time: 8 h
Yield: 111.5 %

Procedure:
1,1-Dimethylethyl 4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidine carboxylate (D2, 546 mg, 1.14 mmol) was dissolved in dichloromethane (10 mL) at rt. HCl (10 mL, 40 mmol, 4 M in 1,4-dioxane) was added and the reaction was stirred overnight. It was then concentrated by rotary evaporation to give a pale brown solid. The residue was dissolved in methanol/dichloromethane and purified by SCX (5 g, eluting with methanol, followed by 2 M ammonia in methanol). The ammonia/methanol fraction was concentrated by rotary evaporation to give 6-fluoro-5-methyl-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one (D3, 318 mg, 72% purity, 80% yield) as an orange oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH3:100][N:101]1[CH:105]=[C:104]([CH2:106][NH2:107])[N:103]=[CH:102]1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:107][CH2:106][C:104]4[N:103]=[CH:102][N:101]([CH3:100])[CH:105]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: Cn1cnc(CN)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cn(C)cn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with C-(1-methyl-1H-imidazol-4-yl)-methylamine. MS (ES+) m/e 732.54 (MH+).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[O:6]=[P:7]12[O:18]P3(OP(OP(O3)([O:14]1)=O)(=O)[O:8]2)=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2:36].[Ca+2].[Ca+2].[Ca+2].[Ca+2]>O>[P:7](=[O:6])([OH:18])([OH:14])[OH:8].[OH2:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Ca+2:36].[Ca+2:36].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [F-]
Solvent: O
Product: O=P(O)(O)O
Product: O=S(=O)([O-])[O-]
Temperature: 129.44444444444446 °C

Procedure:
Concentrated sulfuric acid containing 93% by weight of H2SO4 was continuously pumped to a mixing tee. Also continuously added to the mixing tee was gypsum pond water containing about 0.9% by weight of P2O5, about 0.2% by weight of CaO (2,000 ppm), and about 0.4% H2SO4 and having a pH of about 2.3. Sufficient amounts of gypsum pond water were added to the concentrated acid to produce a diluted acid having about 72% by weight of H2SO4. The diluted acid at a temperature of about 265° F was then cooled in a shell-and-tube heat exchanger through which cooling water flowed on the shell side. The diluted acid, at an exit temperature of about 140° F, was fed directly to a digestion tank containing ground phosphate rock to produce wet phosphoric acid and by-product calcium sulfate hemihydrate. The process was operated for five days, during which the following data was obtained periodically:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH3:1][C:2]1([CH3:9])[CH2:8][C@@H:7]([OH:6])[C@H:5]([NH:18][C@@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[CH2:4][O:3]1.[CH3:1][C:2]1([CH3:9])[CH2:8][C@H:7]([OH:6])[C@@H:5]([NH:18][C@@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[CH2:4][O:3]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1(C)CC2OC2CO1
Solvent: CC(C)O
Product: C[C@@H](N[C@@H]1COC(C)(C)C[C@H]1O)c1ccccc1
Product: C[C@@H](N[C@H]1COC(C)(C)C[C@@H]1O)c1ccccc1
Temperature: 80 °C
Reaction time: 144 h

Procedure:
A mixture of 4,4-dimethyl-3,7-dioxa-bicyclo[4.1.0]heptane (7.0 g, 54 mmol) and (R)-1-phenylethanamine (9.9 g, 82 mmol) in isopropanol (50 mL) was stirred at 80° C. for 6 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elute:petroleum ether:dichloromethane containing 1% ammonia-methanol (7 M), 10:1 to dichloromethane containing 1% ammonia/methanol (7 M) to afford (4R,5R)-2,2-dimethyl-5-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-4-ol (6a) (more polar fraction, 1.5 g) and (4S,5S)-2,2-dimethyl-5-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-4-ol (6b) (less polar fraction, 1.7 g) as a yellow oil. Note: The absolute configuration of the products was assigned randomly. MS (ES+) C15H23NO2 requires: 249, found: 250 [M+H]+. Mobile phase for TLC: ethyl acetate/dichloromethane=2/1.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[Na+].O>CS(C)=O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
10.4 g of 4-hydroxy-carbazole (57 mmol) were dissolved in 31.1 ml of DMSO. 6.9 ml of epichlorohydrin (88 mol) were added and next 57 ml of a 1 N sodium hydroxide solution. The mixture was stirred for 8 h at 40° C. It was cooled to 20° C. and 130 ml of water were added. The product was filtered under suction, and washed with 3×30 ml water. The crude material was recrystallized from isopropanol. The substance was dried at 60° C. for 12 h.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O.O>O1CCOCC1>[NH2:1][C:2]1[C:10]([I:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(N)ccc1C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N)c(I)cc1C(=O)O
Yield: 49.1 %

Procedure:
To a stirred and heated (25° C.) solution of 5 g of 4-amino-2-methoxy benzoic acid in 75 ml of 1,4-dioxane were added 6.9 g of grinded 1-iodo-2,5-pyrrolidinedione. The mixture was stirred in an oil bath at 105° C. for 3 hours. After the addition of 300 ml of water, the crystallized product was filtered off and dried, yielding 4.3 g (48.9%) of 4-amino-5-iodo-2-methoxybenzoic acid; mp. 180.6° C. (interm. 5).
Reaction SMILES: C(OC([N:7]1[CH2:11][CH:10]([F:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([C:16]1[CH2:22][C@H:21]2[N:18]([C:19](=[O:26])[C@@H:20]2[C@H:23]([OH:25])[CH3:24])[C:17]=1[C:27]([O:29]CC=C)=[O:28])[CH3:15])=O)C=C.N1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][CH:10]1[CH2:11][NH:7][C@H:8]([CH:13]=[C:14]([C:16]2[CH2:22][C@H:21]3[N:18]([C:19](=[O:26])[C@@H:20]3[C@H:23]([OH:25])[CH3:24])[C:17]=2[C:27]([OH:29])=[O:28])[CH3:15])[CH2:9]1
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2CC(F)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=C[C@@H]1CC(F)CN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Yield: 20.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S)-1-allyloxycarbonyl-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.7 g), morpholine (694 μl), and triphenylphosphine (199 mg) in tetrahydrofuran (30 ml) and ethanol (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (263 mg) at room temperature. After stirring for an hour, the precipitate was filtered, washed in turn with dichloromethane (3 times) and acetone (twice), and dried under reduced pressure to give (5R,6S)-3-[2-{(2S)-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (248 mg).
Reaction SMILES: [CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([O:14]C1CCCCO1)[CH2:12]2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C(O)=O>CO>[CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:14])[CH2:12]2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC=CC1C2CC(OC3CCCCO3)CC12
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCCCCC=CC1C2CC(O)CC12

Procedure:
A solution of 8.5 g. of 6-(1-heptenyl)-3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane (from Example 12) and 700 mg. of oxalic acid in 350 ml. of methanol is stirred at room temperature (about 25° C.) for 7 days. The solution is then evaporated and the residue extracted with diethyl ether. Evaporation of the ether solution gives a quantitative yield of 6-(1-heptenyl)-bicyclo[3.1.0]hexan-3-ol; γ 3375, 3050, 3025, 1625, 1070, 1020, 960, 850 and 725 cm-1.; γ max 197 mmu (heptane), δ 5.2, 4.8 p.p.m. Thin layer chromatographic analysis shows four spots (silica gel, developed with benzene-ether 5:1).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]1=[O:27].NCCN>O1CCOCC1.[Cu]I>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[C:22]1=[O:27]
Reactant: CN1CCCNC1=O
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCN(C)C1=O
Temperature: 110 °C
Reaction time: 19 h

Procedure:
16.1 g (76.1 mmol) of potassium phosphate and 0.362 g (1.90 mmol) of copper(I) iodide are initially charged, and the apparatus is baked out and then flushed with argon. 10.0 g (38.1 mmol) of 1-iodo-2-methyl-4-nitrobenzene, 6.51 g (57.0 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one and 0.394 g (3.80 mmol) of N,N′-dimethylenediamine in 200 ml of dioxane are added, and the mixture is stirred at 110° C. After 19 h, after cooling, the mixture is filtered with suction through kieselguhr and then washed three times with 100 ml of ethyl acetate. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (2:1→1:1 cyclohexane/ethyl acetate). This affords 5.94 g (63% of theory) of the desired compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([S:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[N:22]=[CH:21][C:20]=2[C:34](O)=[O:35])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH2:48])[CH2:45]2.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH:48][C:34]([C:20]1[CH:21]=[N:22][N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[C:19]=1[S:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:35])[CH2:45]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (199 mg, 1.04 mmol) was added in one portion to 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate#93) (300 mg, 0.87 mmol), 2-Adamantanamine hydrochloride (179 mg, 0.95 mmol), 1-Hydroxybenzotriazole (140 mg, 1.04 mmol) and N-Ethyldiisopropylamine (0.450 mL, 2.60 mmol) in DMF (7 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 18 hours.