Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[C:25](=[CH2:27])[CH3:26].[Li+].[Cl-].[F-].[K+]>CN(C=O)C.O.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>[CH3:26][C:25](=[CH2:24])[CH2:27][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cc1cn2c(n1)C(OC1CCN(C)CC1)c1ccccc1CC2
Temperature: 80 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (100 mg, 0.24 mmoles) in DMF (4 mL) in a screw-capped vial under argon are added methallyltributyltin (331 mg, 0.96 mmole), Pd(PPh3)4 (28 mg, 24 μmole), LiCl (51 mg, 1.2 mmoles). The reaction mixture is heated at 80° C. for 5 hours. A solution of 10% KF in water is added, and the aqueous phase is extracted three times with CH2Cl2. The organic phase is washed with a solution of 10% KF in water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (96.5:3.5:0.35). As the residue is contaminated with tin salts, 1N aqueous HCl is added, and the aqueous phase is extracted three times with Et2O. The aqueous phase is basified to pH 10 with 12N NaOH and the aqueous phase is extracted three times with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure to afford 2-(2-methyl-allyl)-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reaction time: 48 h
Yield: 86.4 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (20.5 g, 73.4 mmol) was dissolved in anhydrous pyridine (140 mL) at room temperature prior to the addition of trityl chloride (20.46 g, 73.4 mmol) in one portion. The reaction mixture was stirred for two days. Pyridine was evaporated and the residue was dissolved in EtOAc. The solution was washed with water (2×) followed by brine. The combined aqueous layer was re-extracted with EtOAc. This organic layer was washed with brine. The combined organic layer was then dried over anhydrous Na2SO4 and evaporated to get an oily residue which yielded white crystalline product from EtOAc and hexane. The mother liquor was chromatographed (400 g silica gel eluted with 20% EtOAc/hexane followed by 40% and finally 70%). The desired regioisomer, benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate (33.08 g, 63.4 mmol, 86% yield) was obtained as a white solid. MS found [M−H]−=520.2 (AP/CI). 1H-NMR (400 MHz, CDCl3) δ, ppm 7.4 (d, J=7.12 Hz, 6H), 7.19-7.34 (m, 15H), 5.25-5.31 (m, 1H), 4.98-5.09 (m, 2H), 3.92 (s, 1H), 3.66 (bs, 1H), 3.14-3.24 (m, 1H), 2.97 (dd, J=9.41, 4.83 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (d, J=11.9 Hz, 2H), 1.76-1.84 (m, 1H), 1.36-1.49 (m, 2H), 1.39-1.43 (m, 1H), 1.19-1.30 (m, 1H). A small amount of the undesired isomer, benzyl (1S,2R,4R)-2-(hydroxymethyl)-4-(trityloxy)cyclohexyl carbamate (1.17 g, 2.243 mmol, 3.06% yield) was also obtained. MS found [M−H]−=520.2 (AP/CI). 1H-NMR (400 MHz, CDCl3) δ, ppm 7.48 (d, J=7.12 Hz, 6H), 7.32-7.40 (m, 5H), 7.21-7.32 (m, 10H), 5.05-5.14 (m, 2H), 4.96 (d, J=8.65 Hz, 1H), 3.89 (dd, J=8.39, 2.8 Hz, 1H), 3.84 (dd, J=10.7, 4.58 Hz, 1H), 3.46 (ddd, J=14.5, 9.92, 4.07 Hz, 1H), 3.07 (ddd, J=15.26, 10.43, 4.3 Hz, 1H), 1.66 (dd, J=14.24, 3.05 Hz), 1.43-1.51 (m, 1H), 1.30-1.40 (m, 2H), 1.14-1.23 (m, 1H), 0.79-0.91 (m, 1H), 0.72-0.79 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18].[F-].[K+]>O1CCCC1.CCCCCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[Sn:17]([CH3:19])([CH3:18])[CH3:16]
Reactant: C[Sn](C)(C)Cl
Reactant: C1=COc2ccccc2O1
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Sn](C)(C)C1=COc2ccccc2O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
14.91 mmol of 1,4-benzodioxine are dissolved in 18 ml of anhydrous tetrahydrofuran under an anhydrous atmosphere, and the temperature of the solution is lowered to −78° C. 23.86 mmol of a 1.5M solution of n-butyllithium in hexane are added dropwise to the reaction mixture, which is stirred at −78° C. for 2 hours 15 minutes. 37.28 mmol of trimethyltin chloride dissolved in 10 ml of anhydrous tetrahydrofuran are added dropwise and the reaction mixture is stirred at −78° C. for 45 minutes and then returned to ambient temperature for 15 hours. The reaction mixture is hydrolysed with 15% aqueous potassium fluoride solution and is stirred for 45 minutes. The precipitated tin salts are removed by filtration, and the aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined and concentrated. Purification by flash chromatography over silica gel (petroleum ether/ethyl acetate: 95/5) allows the expected product to be obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[N:26]=[CH:25]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=4)[N:3]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Yield: 20.7 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-5-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (158 mg, 0.349 mmol), 4-aminobenzamide (100 mg, 0.735 mmol) and TMSCl (0.300 mL, 2.37 mmol) in nBuOH (3 mL) was stirred at 135° C. for 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 4-(4-(1-methyl-1H-indazol-5-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])c(F)c3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(CCN2CCN(c3ccc(N)c(F)c3)CC2)cc1

Procedure:
1-(3-Fluoro-4-nitrophenyl)-4-(4-nitrophenethyl)piperazine (0.19 g) and 10% palladium on carbon (150 mg) were hydrogenated at 4 atmospheres and 60° until completion of hydrogen uptake. The catalyst was then filtered off, the solvent evaporated, and the residual product (0.06 g) used directly in the next stage.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[CH:13]2.O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[CH3:19][N:15]1[C:16]2[C:12](=[CH:11][C:10]([NH:9][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1ccc2cc(Nc3ccncc3)ccc21
Yield: 53.3 %

Procedure:
4-Chloropyridine hydrochloride (8 g) was added to a solution of 5-amino-1-methylindole (7 g) in 75 ml 1-methyl-2-pyrrolidinone preheated to 100° C. The addition of 4-chloropyridine hydrochloride (4 g) after one hour caused no further reaction as determined by TLC. After two hours the reaction mixture was cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and evaporated to 12.7 g of an oil. The oil was eluted through silica with 10% methanol in dichloromethane via flash column chromatography to give the product which was triturated with ether to yield 5.7 g of a solid, m.p. 202°-203° C. Recrystallization from acetonitrile yielded 5 g of product as crystals, mp 209°-211° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[H-].[Na+].[CH3:42][CH:43]([OH:45])[CH3:44].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH:43]([O:45][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)(=[O:16])=[O:15])[N:3]=1)([CH3:44])[CH3:42]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(Br)c3ccccc3c2C)cc1
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)nc(OC(C)C)c2ccccc12
Yield: 61.6 %

Procedure:
To a suspension of ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (93.5 mg, 0.15 mmol) prepared in Example 9-(1) and sodium hydride (60.0 mg, 1.5 mmol) in tetrahydrofuran (2 mL) was added 2-propanol (0.115 mL, 1.5 mmol) under argon atmosphere, and the mixture was heated to reflux for 4 hours. The mixture was neutralized by 2 mol/L hydrochloric acid, and then thereto was added chloroform. The mixture was stirred, and then separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=2%→10%) to give 4-({(1-isopropoxy-4-methylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (53.1 mg, 58%) as a brown powder.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH2:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:26].O>CN(C=O)C.[Pd]>[ClH:26].[NH2:1][C@@H:2]([C:13]([NH2:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12

Procedure:
Z-D-Trp-NH2 (3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH2 as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].Cl>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCN(CCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 95 mg (0.244 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-1,4-diazepane and 30 μl (0.321 mmol) of 3-chloropropan-1-ol. The product is in the form of the hydrochloride.
Reaction SMILES: F[B-](F)(F)F.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][S+:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)C2C=CC=CC=2)=[CH:9][CH:8]=1.[F:29][Sb-:30]([F:35])([F:34])([F:33])([F:32])[F:31].[Na+]>C(Cl)Cl>[F:29][Sb-:30]([F:35])([F:34])([F:33])([F:32])[F:31].[Cl:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][S+:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:11][C:10]2[CH:27]=[CH:28][CH:7]=[CH:8][CH:9]=2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(C[S+](Cc2ccc(Cl)cc2)c2ccccc2)cc1
Agent: F[B-](F)(F)F
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccccc2)Cc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 178.1 %

Procedure:
A mixture of 7.0 g (15.2 mmol) of di-(4-chlorobenzyl)-phenylsulfonium tetrafluoroborate and 25 ml of methylene chloride is dissolved under N2 in a 100 ml round-bottomed flask to give a clear solution and the solution is cooled to 0°-5° C. 5.9 g (22.8 mmol) of sodium hexafluoroantimonate are added at this temperature and the mixture is stirred for about 3 h. The reaction mixture is filtered and the filtrate is freed from the solvent on a rotary evaporator. 50 ml of deionized water are now added to the residue and the product is crystallized out. It is left to crystallize at 0°-5° C. for 1-2 h. The crystals now obtained by filtration are washed with water and dried under a high vacuum at RT overnight. 8.26 g of di-(4-chlorobenzyl)-benzylsulfonium hexafluoroantimonate are obtained as white crystals of melting point 75°-77° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: NCc1c(Cl)cccc1Cl
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2c(Cl)cccc2Cl)c(=O)c1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To 2,6-dichlorobenzylamine hydrochloride of Example 4, Step 2 (1.06 g 5.0 mmol) in tetrahydrofuran (10 mL) was added triethyl amine (0.505 g, 5.0 mmol) followed by 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1.20 g, 5.0 mmol, Example 3) and stirring was continued at room temperature for approximately 16 hours. The reaction mixture was freed of solvent and the residue was triturated successively with water and with diethyl ether, and then dried. The resulting light yellow solid was recrystallized from acetonitrile three times to provide 0.755 g (44%) of the title compound as a white solid: mp 239°-241° C. (dec); 1H NMR (DMSO-d6): δ7.57 (m, 1H), 7.55 (m, 1H), 7.52 (br m, 1H),m 7.43 (m, 1H), 7.30 (s, br, 1H), 5.07 (d, 2H), 1.65 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 3250, 1785, 1660 cm-1 ; MS (m/z) 340/342/344 (M+). HPLC indicates a major component (99.7%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@@:7]23[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:8]2[O:9]C(=O)O3)=[CH:5][CH:4]=[N:3]1>C1COCC1.[C].[Pd]>[CH3:1][N:2]1[C:6]([C@@H:7]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:8]2[OH:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@@]12CCCC[C@@H]1OC(=O)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1nccc1[C@@H]1CCCC[C@@H]1O
Yield: 21 %

Procedure:
A solution of the (3aS,7aS)-3a-(1-methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one (500 mg, 2.25 mmol) prepared in Example 167a and palladium carbon (10%; 500 mg) in THF (10 mL) was stirred at 60° C. for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=2:1) to yield the title compound (85 mg, 21%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:42][N:43]([CH:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:44](=[O:59])[CH:45]([NH:57][CH3:58])[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17](=[O:19])[N:57]([CH3:58])[C@@H:45]([C:44](=[O:59])[N:43]([CH3:42])[C@@H:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1COCC(=O)O
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 2-(carboxymethoxymethyl)piperidine-1-carboxylic acid tert-butylester (225 mg, 0.82 mmol) in 5 ml of dichloromethane was added 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg, 0.90 mmol) and the mixture was to stired for 30 min. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mmol) in dichloromethane (5 mL) was added followed by diisopropylethylamine (0.14 ml, 0.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (20 g) with ethyl acetate to give 416 mg of 2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:30](OC)=[O:31])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[Cl:29])[CH2:18][CH2:19][CH2:20][N:13]21.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(#N)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:30]=[O:31])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[Cl:29])[CH2:18][CH2:19][CH2:20][N:13]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Yield: 84.7 %

Procedure:
To a suspension of lithium aluminum hydride (53.7 mg, 1.42 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (210 mg, 0.472 mmol) in tetrahydrofuran (5 mL) at 0° C., and the resultant mixture was stirred at 0° C. for 5 min. After sodium sulfate decahydrate (500 mg) was added at 0° C., the resultant mixture was filtered and concentrated in vacuo to give a crude solid. To a solution of the crude solid in acetonitrile (5 mL) and dimethylsulfoxide (1 mL) was added Dess-Martin reagent (240 mg, 0.566 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 30 min, diluted with aqueous sodium bicarbonate and ethyl acetate, filtered and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (166 mg, 0.400 mmol, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:17]2[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COc1ccnc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccnc(-c2cccc([N+](=O)[O-])c2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
To a suspension of 2-bromo-4-methoxypyridine (483 mg), 3-nitrophenylboronic acid (643 mg) and tetrakis(triphenylphosphine)-palladium (148 mg) in 1,2-dimethoxyethane (10 ml) was added 2M aqueous solution of sodium carbonate (2.78 ml). The mixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g, 50-100% dichloromethane in n-hexane) to give 3-(4-methoxypyridin-2-yl)-nitrobenzene (365 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1S(O)(=O)=O)([O-])=O.[N+:14]([C:17]1[CH:18]=[C:19](S(O)(=O)=O)[CH:20]=[CH:21][CH:22]=1)([O-])=O.[OH-].[Na+].N(C1C=CC=CC=1)NC1C=CC=CC=1.S(=O)(=O)(O)O>[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:20]2[CH:19]=[CH:18][C:17]([NH2:14])=[CH:22][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(-c2ccc(N)cc2)cc1

Procedure:
A 2-nitrobenzenesulfonic acid derivative (e.g. sodium 2-nitrobenzenesulfonate) or a 3-nitrobenzenesulfonic acid derivative (e.g. sodium 3-nitrobenzenesulfonate) is treated with zinc dust in the presence of an alkali (e.g. sodium hydroxide) and the resulting hydrazobenzene derivative is treated with sulfuric acid to give the corresponding 4,4′-diaminobiphenyl derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.