Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([NH2:24])=[O:23])=[CH:19][C:18]=3[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([NH2:24])=[O:23])=[CH:19][C:18]=3[CH:25]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1
Agent: Cl
Product: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1

Procedure:
1 g of 5-(4-tert-butoxycarbonyl-1-piperazinyl)-benzofuran-2-carboxamide is dissolved in 50 ml of methanolic HCl and stirred for I hour. After customary working up, 5-(1-piperazinyl)benzofuran-2-carboxamide, m.p. 252°-255°, is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11]O1)([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:22].O>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][S:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(CC2CS2)cc(C(C)(C)C)c1O

Procedure:
A solution of 26.2 g [0.10 mol] of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane [Example 1] and 8.4 g [0.11 mol] of thiourea in 100 ml of methanol is stirred for 12 hours at room temperature and subsequently poured into water. Extraction of the aqueous phase with chloroform, drying over sodium sulphate and evaporation of the solvent yields crude 3,5-di-tert.-butyl-4-hydroxybenzyl-thiirane, which after recrystallization from petroleum ether melts at 62°-63° C.
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)C=CC=CC=1.N#N>CC(C)=O.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Agent: [Pd]
Agent: N#N
Solvent: CC(C)=O
Product: Oc1ccc2cc[nH]c2c1
Reaction time: 16 h
Yield: 72.5 %

Procedure:
6-Phenylmethoxyindole (3.93 g, 17.6 mmol), was suspended in acetone (350 mL), under N2 and cooled in an ice bath. 10% Palladium on carbon (0.80 g) was added, and the N2 atmosphere was replaced with H2 by alternately placing the reaction flask under vacuum and introducing H2 from a balloon. The cold bath was then removed and the reaction mixture stirred under positive H2 pressure for 16 hours. The reaction mixture was cooled in an ice bath, and N2 reintroduced. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give 6-hydroxyindole (1.70 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][C:43]([CH3:59])([CH3:58])[C:44]([NH:46][NH:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=1)=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][C:43]([C:44](=[O:45])[NH:46][NH:47][C:48](=[O:57])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([CH3:58])[CH3:59])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (60 mg) (0.101 mmol) and 40 mg (0.1318 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed at room temperature in a high vacuum. The residual oil is treated with water and the precipitated product is filtered off. The whole is washed in succession with water, ethanol and diethyl ether and dried at room temperature in a high vacuum. There are obtained 62 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
(Method 1) 3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at 170° C. for 17 hr. The reaction mixture was suspended in ethyl acetate (500 mL) and distilled water (200 mL). The insoluble matters were removed by Celite filtration and washed twice with ethyl acetate (300 mL×2). The organic layer was washed once with an aqueous solution of disodium EDTA (200 mL) and twice with saturated brine (200 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)C(C)(F)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)C(C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=505(M+H+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])/[CH:23]=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:39]>CO>[CH3:25]/[C:24](/[C:26]1[CH:27]=[C:28]([C:32]([NH2:33])=[NH:39])[CH:29]=[CH:30][CH:31]=1)=[CH:23]/[C:22](=[O:34])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: C/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CO
Product: C/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (90 mg, 0.19 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1Z)-1-methyl-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)-benzenecarboxamidine (35 mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 435.1
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl>[CH3:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([C:23]3[NH:27][C:26]([C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[CH:25][CH:24]=3)[CH:9]=2)[O:5][C@@H:4]([CH3:33])[CH2:3][OH:2])=[CH:18][CH:17]=1)(=[O:21])=[O:20]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Under nitrogen atmosphere, 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (88.8 mg, 0.183 mmol) synthesized in Example (1i) was dissolved in dichloromethane (5 mL), and a boron tribromide/dichloromethane solution (1.0M, 220 μL, 0.22 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 30 minutes. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (52.2 mg, yield 61%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.O>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1[S:5][CH2:4][CH2:3][NH2:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: NCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1c(SCCN)n(Cc2ccccc2)c2ccccc12

Procedure:
2-Aminoethanethiol hydrochloride (0.419 g, 3.12 mmol) was added to a stirred suspension of sodium hydride (0.314 g, 50% in mineral oil, 6.56 mmol) in anhydrous dimethylformamide (30 ml) and after 1 hour, 1-benzyl-2-chloro-3-methylsulfonylindole (1.0 g, 3.29 mmol) was added. One half hour thereafter the solution was diluted with water, the product extracted with ether, the extract dried over sodium sulfate and evaporated in vacuo. The product was obtained as a solid, M.P.-95°-96°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:10]2[CH:11]=[C:2]([F:1])[CH:3]=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccc(Cl)cc1F
Yield: 42.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (150 mg, 0.93 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (250 mg, 1.11 mmol) and DMAP (cat.) gave the title compound (140 mg, 43%) after purification by column chromatography with DCM/n-hexane (4:1) as the eluent.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:19][C:20](=[O:27])[C@@H:21]([OH:26])[CH2:22][S:23][CH2:24][CH3:25])[CH:17]=[CH2:18].[C:28]([S:31][CH2:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([O:19][C:20](=[O:27])[C@@H:21]([O:26][C:34](=[O:35])[C@H:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH2:22][S:23][CH2:24][CH3:25])[CH:17]=[CH2:18]
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Reactant: C=CCOC(=O)[C@@H](O)CSCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](CSCC)OC(=O)[C@H](C)CSC(C)=O
Reaction time: 8 h

Procedure:
Dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) in dichloromethane (20 ml) was added to a stirred solution of the product of step b) (0.95 g, 5 mmol), (S)-3-(Acetylthio)-2-methylpropanoic acid (0.81 g, 5 mmol) and 4-(dimethylamino)pyridine (0.06 g, 0.5 mmol) in dichloromethane (30 ml). The mixture was stirred overnight, filtered and the solvent evaporated. The residue was dissolved in ethyl acetate, filtered and washed with potassium hydrogen sulphate solution, sodium bicarbonate solution and brine and the solvent evaporated. Chromatography on silica with ethyl acetate/petroleum ether as eluant gave the sub-title compound (1.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO[C@@H]1CCCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-({[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 15 (0.30 g, 0.42 mmol) in DCM (17 mL) was added trifluoroacetic acid (0.84 mL, 10.9 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-[(3R)-piperidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 3 (Table 1) (0.045 g, 29.41%) as a white solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A suspension of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 1.76 g, 6.05 mmol), 1-(benzyloxy)-4-isocyanatobenzene (1.50 g, 6.66 mmol) and triethylamine (2.11 mL, 15.1 mmol) in THF (15 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide N-[4-(benzyloxy)phenyl]-4-(2-tert-butylphenyl)piperazine-1-carboxamide (2.65 g, 99%) as a off white solid.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[NH:11])[NH:3]1.C1(C2CCCCCCCCCC=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14]N=1>[Ni](Cl)Cl.CO>[CH:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:2]3[N:1]=[C:15]4[N:14]=[C:22]([C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=54)[N:11]=[C:4]4[NH:3][C:2]([C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=54)=[N:1][C:15]4=[N:14][C:22]([C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=54)=[N:11][C:4]=2[NH:3]3)[CH:9]=1
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: N=C1NC(=N)c2ccccc21
Agent: Cl[Ni]Cl
Solvent: CO
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 25 °C
Yield: 28.5 %

Procedure:
In 20 g of n-amylalcohol were dissolved 10 g (0.02865 mole) of the diiminoisoindoline of the formula (XXXII) and 4.36 g (0.02863 mole) of diazabicycloundecene, to which 0.92 g (0.0071 mole) of nickel chloride was added. The mixture was then heated under reflux for 30 hours. The reaction mixture was then cooled to room temperature and poured into 120 ml of methanol. The crystals thus precipitated were washed with a small amount of methanol and the resulting crystals were purified with a chloroform/THF (=9/1 (weight ratio))/silica gel column to obtain 2.1 g (yield: 25.2%) of a phthalocyanine compound of the formula (XXIII) below. This compound showed max in toluene of 749 nm and logC- of 5.10. The IR spectrum of this compound is shown in FIG. 9. ##STR54##
Reaction SMILES: Br[C:2]1[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][S:5][CH:6]=1.[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:4][S:5][CH:6]=4)=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1cscc1Br
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4cscc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(4-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([C@@H:7]1[O:9][CH2:8]1)[Cl:6]>C1COCC1.B(F)(F)F.CCOCC>[Cl:1][CH2:2][C@H:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: OCCCl
Reactant: ClC[C@H]1CO1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H](CCl)COCCCl
Temperature: 45 °C
Yield: 866.9 %

Procedure:
2-chloroethanol (34.8 g, 43.2 mmol) and boron trifluoride diethyl etherate (0.136 mL, 1.08 mmol) were dissolved in 20 mL of THF and cooled in an ice bath. (R)-(−)-epichlorohydrin (10.0 g, 10.8 mmol) in 10 mL of THF was added slowly through a syringe. After the addition, the ice bath was removed and the mixture was heated in a 45° C. oil bath for 90 min at which time the reaction was complete. The reaction was concentrated in vacuo to give an oily crude product (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (2I, 16.2 g, 86.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56-3.71 (m, 6H) 3.85-3.92 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23](Cl)=[N:24][OH:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccc(F)cc4)o3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and (5-(4-fluorobenzyl)-furan-2-yl)acetohydroximoyl chloride (161 mg, 0.602 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (45 mg, 33%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1.C([O-])(O)=O.[Na+].[C:13](Cl)(Cl)=[S:14]>C(Cl)(Cl)Cl>[N:1]([CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: NCc1ccoc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=NCc1ccoc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of 3-(aminomethyl)furan (0.565 g, 5.818 mmol) in 10 mL of CHCl3 at 0° C. was added 10 mL of a saturated NaHCO3 solution and thiophosgene (0.66 mL, 8.66 mmol). The reaction mixture was stirred vigorously for 45 min while maintaining the temperature at between 0°-5° C. The phases were then separated and the aqueous layer extracted with CHCl3 (10 mL). The combined organic solutions were dried (MgSO4), filtered, and the volatiles removed by blowing a gentle stream of nitrogen over the solution. Traces of residual solvent and thiophosgene were then evaporated off under high vacuum (20° C./0.05 mm Hg) to afford 0.659 g,(81 percent of theoretical) of 3-(isothiocyanatomethyl)furan as a dark orange liquid which was found to be pure by NMR and suitable for use in the Diels-Alder step: 1H NMR (300 MHz, CDCl3) d 7.45 (s, 1H), 7.42 (s, 1H), 6.42 (s, 1H), 4.54 (s, 2H); 13C NMR (75 MHz, CDCl3) d 144.0, 139.9, 132.7, 119.5, 109.4, 40.2 ; IR (neat) 2090, 1595 cm-1; MS m/e 139, 81 (base).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) and triethylamine (0.23 g, 2.1 mmol) in dichloromethane (10 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of benzenesulfonyl chloride (0.37 g, 2.1 mmoL) in dichloromethane (1 mL) was added under to the mixture while stirring. After 2 hours, the reaction mixture was quenched with water. The separated organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was crystallized from ethyl acetate/hexanes to give 2,2,2-trifluoro-N-[4-(1-benzenesulfonyl-piperidin-4-ylmethyl)-phenyl]acetamide (0.43 g, 57%), m.p. 194–195° C.; Analysis for C20H21N2O3SF3: Calc.: C, 56.32; H, 4.96; N, 6.57; Found: C, 56.54; H, 4.99; N, 6.68.