Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:38][C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][N:29]=[C:28]2[Cl:27])=[CH:33][CH:34]=1
Reactant: Cc1ccc2ccnc(Cl)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2ccc(CBr)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added to a solution of 1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL). The resulting mixture is heated to reflux for 6 hours then cooled to room temperature and diluted with methylene chloride. The organic layer is washed with 1N NaOH and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes to give the product (1.4 g, 5.46 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH3:17])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1O

Procedure:
5-Methylsalicylic acid was reacted with methanol and sulphuric acid by the general method of Brunner (Monatsh. 1913, 34, 916) to give methyl 5-methylsalicylate, b.p. 115°-116° C./10 mmHg. This ester (12.0 g) was heated together with benzyl chloride (9.1 g) and anhydrous potassium carbonate (5.0 g) in dry sulpholane (90 ml) at 100° C. for 22 hours. The mixture was then poured into a mixture of ice and water (1200 ml) to give crude methyl 2-benzyloxy-5-methylbenzoate (17.6 g). This ester (4.3 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 100 ml) for 2 hours and the mixture was then cooled, diluted with water, and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-5-methylbenzoic acid (3.65 g), m.p. 98°-100° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:17]2([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:20][CH2:19][CH2:18]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCC2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (2.00 g, 8.30 mmol) in methanol (10 mL) was added cyclobutanone (294 mg, 4.20 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was heated under reflux for 6 hours. The solvent was distilled off from the mixture. The resulting residue was purified by a flash column chromatography to synthesize bis(3,5-di-t-butyl-4-hydroxyphenylthio)cyclobutane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:46][C:47]=1[Cl:48])\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18][CH2:19][C:20]([CH2:41][Cl:42])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:66])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:46][C:47]=1[Cl:48])\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:66])[CH2:19][C:20]([CH2:41][Cl:42])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c(Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c(Cl)s1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (29.9 g, 34.7 mmol) in Dichloromethane (DCM) (1.1 L) at −40° C. was added dropwise a solution of m-CPBA (8.17 g, 36.5 mmol) in Dichloromethane (DCM) (220 mL) over 10 min. The mixture was stirred at the same temperature over 30 min. LCMS indicated completion of the reaction. The mixture was treated with 15% aq. Na2S2O3 (200 mL). The organic phase was separated and washed with 5% NaHCO3 (400 mL), brine (400 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (5R,6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (29 g, 31.8 mmol, 91% yield) as a light yellow solid. LCMS: (M+H)+: 876.3
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: CN1CCNCC1
Product: CN1CCN(c2n[nH]c(=O)c3ccccc23)CC1

Procedure:
4-chlorophthalazin-1-one and 1-methylpiperazine were treated using methods similar to that described in Examples 1A to give the title compound. MS (APCI+) M/Z 245 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][CH2:21][N:15]4[C:14](=[O:22])[CH2:13][CH2:12]3)[CH:18]=2)O1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:43]1[CH:44]=[C:45]([CH2:49][NH:50][S:51]([CH2:54][CH3:55])(=[O:53])=[O:52])[CH:46]=[N:47][CH:48]=1>>[O:22]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][CH2:21][N:15]13)[CH:18]=[C:9]([C:43]1[CH:44]=[C:45]([CH2:49][NH:50][S:51]([CH2:54][CH3:55])(=[O:52])=[O:53])[CH:46]=[N:47][CH:48]=1)[CH:10]=2
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CC1(C)OB(c2cc3c4c(c2)CCC(=O)N4CCC3)OC1(C)C
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c4c(c2)CCC(=O)N4CCC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 45, 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(5H)-one (prepared from 9-bromo-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(51H)-one and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in analogy to the procedure described for the preparation of intermediate A-1 [B]) has been coupled to ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11) to give the title compound as an off-white amorphous solid. MS: 386.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[N:23]1([CH2:29][CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(OCC)(=O)C.C(N(CC)CC)C>[OH:32][CH2:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[C:15]3[CH3:20])=[O:8])[CH2:25][CH2:24]1
Reactant: OCCCN1CCNCC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(CCCO)CC2)c2nccc(C)c2c1
Yield: 95.3 %

Procedure:
A mixture of 4.3 g (0.012 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 3.5 g (0.024 mole) of 1-piperazinepropanol was heated at 120° for 2 hr and allowed to cool. The mixture was diluted with ethyl acetate and excess triethylamine, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness to afford 4.9 g (96%) of the desired compound as a gum. The IR and NMR (CDCl3) were consistent with the assigned structure.
Reaction SMILES: C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:56][O:57][C:58](=[O:90])[NH:59][CH:60]([CH:84]1[CH2:89][CH2:88][O:87][CH2:86][CH2:85]1)[C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78](Br)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62].[C:91]([O:95][C:96]([N:98]1[CH:103]([C:104]2[NH:105][C:106]([C:109]3[CH:114]=[CH:113][C:112](B4OC(C)(C)C(C)(C)O4)=[CH:111][CH:110]=3)=[CH:107][N:108]=2)[CH:102]2[CH2:124][CH:99]1[CH2:100][CH2:101]2)=[O:97])([CH3:94])([CH3:93])[CH3:92]>>[C:91]([O:95][C:96]([N:98]1[CH:103]([C:104]2[NH:105][C:106]([C:109]3[CH:110]=[CH:111][C:112]([C:78]4[CH:77]=[CH:76][C:75]5[C:80](=[CH:81][CH:82]=[C:73]([C:70]6[NH:69][C:68]([CH:64]7[CH2:65][CH2:66][CH2:67][N:63]7[C:61](=[O:62])[CH:60]([NH:59][C:58]([O:57][CH3:56])=[O:90])[CH:84]7[CH2:89][CH2:88][O:87][CH2:86][CH2:85]7)=[N:72][CH:71]=6)[CH:74]=5)[CH:79]=4)=[CH:113][CH:114]=3)=[CH:107][N:108]=2)[CH:102]2[CH2:124][CH:99]1[CH2:100][CH2:101]2)=[O:97])([CH3:94])([CH3:93])[CH3:92]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C1CCOCC1
Yield: 47.8 %

Procedure:
This compound was synthesized using the same procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using [2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.150 g, 0.277 mmol) and 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.155 g, 0.332 mmol) to give 3-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.106 g, 48% yield). LCMS-ESI+: calc'd for C46H53FN7O6: 799.41 (M+); Found: 800.85 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[Li]CCCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[C:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.[Br-].[Zn+2].[Br-].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>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][C:26](=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([O:9][CH3:10])=[CH:6][CH:7]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)c(OC)n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of 2,6-dimethoxypyridine (0.211 g, 1.51 mmol) in dry THF (7 mL) at −78° C. under Ar was added n-BuLi (1.53 M in hexanes, 1.18 mL, 1.81 mmol) dropwise. After the addition, the mixture was stirred at 10° C. for 30 minutes and then it was re-cooled to −78° C. To this mixture was added a solution of (previously fused in vacuo) zinc bromide (0.407 g, 1.81 mmol) in THF (2 mL) and the reaction mixture was allowed to warm to ambient temperature. The resulting mixture was cannulated into a flame-dried flask containing 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.532 g, 1.51 mmol) and Pd(PPh3)4 under Ar. The vessel was sealed and the mixture was heated at 90° C. (oil bath temperature) for 4 h. The cooled mixture was then quenched with saturated NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was then purified by flash chromatography (SiO2/CH2Cl2-hexane, 7:3) to afford the title compound (0.295 g, 48%) as a yellow gum:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[CH:16]=[N:17][C@H:18]([C:24]12[O:31][CH2:30][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:26][O:25]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].O>CCOCC>[F:39][C:15]([F:14])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C@@H:16]([NH:17][C@H:18]([C:24]12[O:25][CH2:26][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:30][O:31]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C[C@H](N=CC(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Temperature: 40 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
1-Bromo-4-fluorobenzene (1.12 g, 6.4 mmol) of was dissolved in ether (20 ml) and cooled to −78° C. nBuLi (2.56 ml, 2.5M, 6.4 mmol) was added and the reaction mixture was stirred for 1 h. (2,2-Difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (1.18 g, 3.2 mmol) was added and stirring was continued for 2 h while the solution was allowed to warm up to 40° C. Water (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The organic layer was separated, washed with brine and was dried over MgSO4. The solvent was evaporated and the crude was purified by flash column chromatography using silica gel and 20:80 ethylacetate:hexane as an eluent to give [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (265 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)C>ClCCl>[CH3:11][C:8]1([CH3:12])[O:7][C@H:6]([C@H:5]2[N:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:3](=[O:21])[C@H:2]2[NH:1][C:29](=[O:30])[CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][O:9]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(N2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
A solution of (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphenyl)azetidin-2-one (12.21 g, 41.8mmol) in dichloromethane (160 ml) was cooled to 0° C. and treated sequentially with phenylacetyl chloride (6.1 ml, 46.1 mmol), then triethylamine (6.4 ml, 45.9 mmol). After stirring at 0° C. for 15min., the mixture was warmed to room temperature and stirred for a further 30 min. The reaction mixture was diluted with dichloromethane and washed twice with water, then brine, The organic layer was dried over magnesium sulphate, filtered and the solvent evaporated in vacuo to yield a solid. Trituration with diethyl ether yielded the title compound (16.16 g, 94%) as a white amorphous solid; [α]D 0.0° (c=1.00 DMF); νmax (KBr) 1757, 1661 and 1510 cm- ; δH (CDCl3) 1.16 (3H, s), 1.25 (3H, s), 3.62 (2H, s), 3.69-3.82 (2H, m), 3.76 (3H, s), 4.02 (1H, m), 4.36 (1H, dd, J 5.5, 4.0 Hz), 5.58 (1H, dd, J 9.4, 5.5 Hz), 6.56 (1H, d, J 9.4 Hz), 6.83 (2H, d, J 8.9 Hz) and 7.25-7.40 (7H, m); m/z (EI) 410 (5); (CI, +ve ion, ammonia) 411 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([N+:16]([O-])=O)=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Yield: 368.3 %

Procedure:
10-Isopropyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (75 mg, 0.30 mmol) in 10 ml EtOH in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (239 mg, 98%). LC/MS (ESI+): 217 (M+H).
Reaction SMILES: CS[CH2:3][C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C[I:16]>ClCCl>[I:16][CH2:3][C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CI
Reactant: CSCc1cc(=O)c2ccccc2o1
Solvent: ClCCl
Product: O=c1cc(CI)oc2ccccc12
Reaction time: 96 h

Procedure:
8 g of 2-methylthiomethyl-4-oxo-4H-chromene, 200 ml of methyl iodide and 26 ml of dichloromethane are brought to reflux with stirring for 4 days. The precipitate is filtered off, the excess solvents and reagents are evaporated off, the residue is taken up with ethyl ether and the organic phase is washed with sodium thiosulfate solution, dried and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NS(C)(=O)=O)c1
Yield: 70 %

Procedure:
Starting with [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester and methanesulfonyl chloride, and using the method analogous to the one described for example 22-1, [4-(3-methanesulfonylamino-benzene-sulfonyl-amino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (15 mg, 70%) was obtained as a white solid. MS cald. for C18H24N4O6S2 456, obsd. (ESI+) [(M+H)+]:457.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5](N)[C:6]2[CH:12]=[N:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7]=2[CH:17]=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@H:28]2[CH2:33][NH:32][CH2:31][CH2:30][NH:29]2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@@H:28]2[NH:29][CH2:30][CH2:31][N:32]([C:12]3[C:6]4[CH:5]=[CH:4][C:3]([CH3:2])=[CH:17][C:7]=4[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[N:11]=3)[CH2:33]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Fc1cccc(CC[C@H]2CNCCN2)c1
Reactant: Cc1cc(N)c2c(c1)Nc1ccccc1N=C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Temperature: 110 °C
Reaction time: 64 h
Yield: 66.3 %

Procedure:
Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-1-ylamine hydrochloride (400.0 mg, 1.54 mmol), (S)-2-[2-(3-Fluoro-phenyl)-ethyl]-piperazine (641.5 mg, 3.08 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), and toluene (2.8 ml). Stir and heat the mixture at 110° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 423.2 mg (66%) of a tan foam: mp 81°, dec; mass spectrum (ion spray): m/z 415.2 (M+1).
Reaction SMILES: C[C:2]([O-:7])=[CH:3][C:4]([CH3:6])=O.C[C:9]([O-])=[CH:10][C:11](C)=[O:12].[Ca+2].COC1C=CC(O)=CC=1>C(O)CCC>[CH2:2]([O:7][C:11](=[O:12])[CH:10]=[CH2:9])[CH2:3][CH2:4][CH3:6]
Reactant: CC(=O)C=C(C)[O-]
Agent: COc1ccc(O)cc1
Agent: [Ca+2]
Solvent: CCCCO
Product: C=CC(=O)OCCCC
Reaction time: 3 h
Yield: 98.5 %

Procedure:
The reaction was performed for 3 hours in the same manner as in Example 2 except adding 0.48 g (0.002 mole) of calcium acetylacetonate and 0.2 g of hydroquinone monomethyl ether instead of zirconium acetyl acetonate and 0.28 g of hydroquinone monomethyl ether. The results were a 99.1% conversion of n-butanol and 98.5% yield of n-butylacrylate. This ester was recovered in a 97.5% yield by direct distillation.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]#[N:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:22][OH:23].C(=O)([O-])O.[Na+]>CCO>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](=[NH:20])[NH:22][OH:23])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(NC3CCOCC3)c(C#N)cnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CCOCC3)c(C(=N)NO)cnc21
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Intermediate 137 (3.50 g, 12.9 mmol), hydroxylamine hydrochloride (3.30 g, 47.8 mmol) and sodium hydrogencarbonate (4.01 g, 47.8 mmol) in EtOH (45 ml) were heated at 45° C. for 1.5 hours then at 50° C. for 2.5 hours. The suspension was concentrated in vacuo and the solid stirred in dichloromethane (80 ml) for 0.5 hours. The mixture was filtered and the solid stirred in EtOH, the resultant mixture was filtered and the filtrate evaporated. The solid was then washed with dichloromethane three time to afford Intermediate 138 as a white solid (1.62 g). LCMS showed MH+=305; TRET=1.85 min
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:21]([OH:23])=[O:22])[CH:12]([C:18]([OH:20])=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH2:14].OS(O)(=O)=O>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH:12]([C:18]([OH:20])=[O:19])[CH2:11][C:21]([OH:23])=[O:22]
Reactant: C=C(C(=O)O)C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(C(=O)O)C(CSc1nc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.45 g of 2-mercaptobenzthiazole and 5 g of but-3-ene-1,2,3-tricarboxylic acid are ground with one another in a mortar. The powdered mixture is introduced in portions and with stirring into 60 ml of 70% H2SO4 at 48°-50°, in the course of one hour. After a further 3 hours at 48°-50°, the reaction mixture is cooled to room temperature and diluted with 250 ml of water at 25°-30°, with stirring. The aqueous solution is decanted from a little tacky deposit and is diluted with a further 200 ml of water. After being stirred for 1 hour the precipitate is filtered off and dried. The 4-(benzthiazol-2-ylthio)-butane-1,2,3-tricarboxylic acid obtained melts at 188°-190° after recrystallisation from methanol/water.