Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 38 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (60 mg, 0.187 mmol), 4-fluoro-5-hydroxy-2-methylindole (46 mg, 0.28 mmol) and cesium carbonate (121 mg, 0.37 mmol) in DMA (2 ml) was heated at 100° C. for 2 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methanol/methylene chloride (5/95) followed by methanol saturated with ammonia/methylene chloride (5/95). The fractions containing the expected product were combined and evaporated. The residue was triturated with a mixture of pentane/ether. The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (32 mg, 38%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:15]4[C:20]=2[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]4[C:20]([C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=2)=[CH:32][CH:33]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)cc1
Yield: 51.5 %

Procedure:
An amount of 3.74 g (10 mmol) of 9,10-diphenylanthracene-2-boronic acid synthesized in the same manner as in Exemplary Synthesis 1, 9.44 g (40 mmol) of p-dibromobenzene, and 300 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 2.32 g (5.15 mmol) of 2-(4-bromophenyl)-9,10-diphenylanthracene. The yield was 51.5%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:23])[CH2:6][C@@H:5]1[OH:24].C(N(CC)CC)C.[O:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[ClH:1].[O:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][C@@H:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:23])[CH2:6][C@@H:5]3[OH:24])[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@@H](NCc2cc3c(cn2)OCCO3)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-{2-[(3S,4R)-4-Amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride (247 mg, 0.6513 mmol) was stirred in 9:1 v:v chloroform:MeOH (10 ml) at rt under argon and triethylamine (318 μL, 3.5 eq.) was added. The mixture was stirred at rt for 10 mins., then 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (108 mg, for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) was added and the mixture was stirred at rt for 2 hours before being treated with sodium triacetoxyborohydride (414 mg) added in one portion. The mixture was then stirred at rt overnight. Saturated aqueous sodium hydrogen cabonate (5 ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 100 ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×50 ml). The combined DCM extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as a white foam (130 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCC(=O)O
Product: O=C(O)CCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 90.3 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and β-alanine (0.115 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.31 g (90%) 141 as a very pale yellow powder: mp=206–208° C.; Rf 0.84 (A): Rf 0.81 (B): Rf 0.55 (D): IR (cm−1): 2800–3125 (OH), 3109 (C═CH), 2646 (C—H), 1780 (C═O), 1718 (bs, C═O), 1621 (C═C), 1536 (N═O), 1441 (C═C), 1395 (C—O), 1346 (N═O), 1228 (C—O), 724 (C═CH); MS m/z (rel intensity) 263 (100), 191 (36).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH2:13]
Reactant: COc1cc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(S(C)(=O)=O)ccc1N
Reaction time: 18 h
Yield: 98.1 %

Procedure:
A suspension of 2-methoxy-4-(methylsulfonyl)-1-nitrobenzene (0.175 g, 0.76 mmol) and palladium on carbon (10 wt %, 0.10 g) in ethanol (10 mL) was stirred under hydrogen at one atmosphere pressure for 18 hours. The reaction was filtered through celite and concentrated to give 2-methoxy-4-(methylsulfonyl)aniline (0.15 g, 92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[C:30][Si](C)(C)C)=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>O1CCCC1>[CH2:7]([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[CH:30])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Potassium carbonate (295 mg, 2.136 mmol), 3,4-bis(benzyloxy)-6-((trimethylsilyl)ethynyl)pyridazine (Intermediate 4; 830 mg, 2.14 mmol) and methanol (10 ml) were added to tetrahydrofuran (5 ml) to produce an orange suspension. The mixture was stirred for 1 hour and then partitioned between brine and ethyl acetate. The organic layer was washed with brine and evaporated before the residue was purified by silica chromatography (eluting with 10-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-ethynylpyridazine (530 mg, 1.68 mmol, 78% yield).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1)=O.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:10]2[CH:11]=[C:7]([C:5]3[CH:4]=[CH:3][N:35]=[C:36]([NH2:38])[N:37]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)=[N:9]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Cn2cc(C(=O)/C=C/N(C)C)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 67.8 %

Procedure:
450 mg (1.1 mmol) of (2E)-3-(dimethylamino)-1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]prop-2-en-1-one were dissolved in 10 ml of dry dimethylformamide and 1.2 g (6.66 mmol) of guanidine carbonate and 910 mg (6.66 mmol) of potassium carbonate were added. After 16 hours at 120° C. the solvent was removed in vacuo and the residue taken up with dichloromethane and washed with water. The organic phase was then dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 300 mg (68%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(N)c(C(=O)O)c1
Yield: 49.3 %

Procedure:
A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (21.0 g, 70.9 mmol) in methanol (210 mL) and palladium/carbon (2 g) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a brown oil, which was stirred in ether (300 mL) overnight. The ether slurry was filtered to give 2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown solid (9.3 g, 49% yield). The product was used in the next step without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[OH:23][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11]
Reactant: COC=CC(C)=O
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)C=C(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
LiHMDS (1M in THF, 100 mL, 2 eq) is added dropwise to a cold (−78° C.) solution of 4-methoxy-3-buten-2-one (10 mL, 100 mmol, 2 eq) in THF (400 mL). After a 30 min stirring at −78° C., a solution of pivaloyl chloride (6.12 mL, 50 mmol) in THF (100 mL) is added. The resulting mixture is allowed to warm to it over 2 h and quenched by addition of a saturated solution of NH4Cl. THF is removed under vacuum. The concentrated mixture is extracted with Et2O. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→85:15) to afford 6.83 g of the title compound as a yellow oil: ESI-MS: 185.1 [M+H]+; TLC: Rf=0.87 (Hex/EtOAc, 1:1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1nc2ccccc2o1
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 3-[3-(piperidinomethyl)phenoxy]propylamine (0.28 g) and triethylamine (0.40 g) in ethanol (2 ml), at 0° C., under nitrogen, was added 2-chlorobenzoxazole (0.17 g). The reaction mixture was stirred for one hour at 0° C., stirred at room temperature for 16 hours, evaporated under reduced pressure and subjected to column chromatography on silica (chloroform:methanol 25:1) to give the title compound as an oil (0.35 g). This was treated with anhydrous oxalic acid (2.1 equivalents) in methanol (5 ml). Addition of diethyl ether gave 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]benzoxazole dioxalate (0.245 g), m.p. 172°-1/4° C. (recrystallised from isopropanol-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@@H:5]1[C:9]([OH:11])=[O:10].C(S)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: CCCCS
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (+)-cis chrysanthemic acid (1.0 g) in toluene (9 g) was added n-butanethiol (107 mg). Irradiation with a high pressure mercury lamp (100 W) was made for one hour. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (0.9 g). The optical isomer ratio of the product was (+)-cis, 3.0%; (-)-cis, 2.1%; (+)-trans, 46.6%; and (-)-trans, 48.3%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](O)=[O:29])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](=[O:29])[NH:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[N:17]=[C:11]2[CH:12]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3cccnc3F)nc2c1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 85.3 %

Procedure:
The product was prepared in the same manner as described in example 44d using 2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (500 mg, 2.18 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (519 mg, 2.62 mmol) as starting materials. The reaction affords 5-[2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (761 mg, 85.2%) as white solid. mp.: 249-251° C., MS: m/z=410.0 (M+H+).
Reaction SMILES: [Br-].[F:2][C:3]([F:32])([F:31])[O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1.[C:33]1([Si:39]2(CCCCC)[CH2:44][CH2:43][CH:42]([CH:45]3[CH2:50][CH2:49][CH:48]([CH:51]=O)[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)C=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:32][C:3]([F:2])([F:31])[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:51][C@H:48]2[CH2:47][CH2:46][C@H:45]([C@H:42]3[CH2:43][CH2:44][Si@H:39]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:40][CH2:41]3)[CH2:50][CH2:49]2)=[CH:29][CH:30]=1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Reactant: FC(F)(F)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
The general procedure of Example 4 was repeated using 4-trifluoromethoxybenzyltriphenylphosphonium bromide and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)cyclohexane carbaldehyde, thereby obtaining trans-4-(trans-4-(2-(4-trifiuoromethoxyphenyl)ethyl)cyclohexyl)-1-n-pentyl-1-silacyclohexane with the following results of IR and 13C-NMR analyses.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4].[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([Cl:28])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Reaction time: 8 h
Yield: 97 %

Procedure:
724 mg of [7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was suspended in 15 ml of N,N-dimethylformamide, and 760 mg of N-chlorosuccinimide was added thereto. The reaction solution was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and 1N hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. Thus, 764 mg of [8-chloro-7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was obtained. This compound was mixed with 4 g of t-butyl piperazine-1-carboxylate. The mixture was heated at 150° C., and stirred for three hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was separated. The organic layer was washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 724 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+].C([O:36]CCOCCO)C>O>[C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)(=[O:36])[NH2:2]
Reactant: N#Cc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.16 g of 6-[4-(4-(5-cyanobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane, 2.4 g of NaOH, 50 ml of H2O and 40 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. The mixture is then cooled to room temperature, worked up in the conventional manner and gives 6-[4-(4-(5-carbamoylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]1=[O:33].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[NH:38]1[C:27]([CH2:26][CH2:25][CH2:24][S:23][C:9]2[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]3[C:6]=2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]3[CH2:29][CH:30]([CH3:31])[CH3:32])=[N:28][N:40]=[N:39]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCc3nnn[nH]3)n(Cc3cccc4ccccc34)cc21

Procedure:
The compound of Example 18, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile (98 mg) was dissolved in toluene (20 ml) and trimethyltin azide (100 mg) was added. The solution was heated under reflux for 110 hours, then the solvent was evaporated and the residue was chromatographed, eluting with ethanol:dichloromethane (1:19), to give the title compound (30 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[Cl:24])[CH:20]=[N:19][CH:18]=[CH:17]3)[CH2:9]1)=O)(C)(C)C>ClCCl.Cl.C(O)(C)C>[ClH:24].[Cl:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][N:19]=[CH:20]2)=[CH:15][C:14]=1[S:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Clc1cc2cnccc2cc1S[C@H]1CCNC1
Yield: 215.5 %

Procedure:
4.5 g (6.1 mmol) (S)-3-(7-Chloro-isoquinolin-6-ylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 15 ml dichloromethane and 7.5 ml 6N HCl in isopropanol were stirred over night. After evaporation water was added and lyophilized. 1.98 g of 7-Chloro-6-((S)-pyrrolidin-3-ylsulfanyl)-isoquinoline hydrochloride were obtained. Rt=0.76 min (Method B). Detected mass: 264.1/266.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CN(C)C=O.Cl[CH2:28][C:29]#[N:30]>C(N(CC)CC)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:28][C:29]#[N:30])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: N#CCCl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC#N)C[C@H]1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a stirred solution of 12.55 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide in 180 parts of N,N-dimethylformamide were added 5.05 parts of N,N-diethylethanamine and 3.4 parts of 2-chloroacetonitrile. The whole was stirred for 18 hours at 50° C. The solvent was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 1,1'-oxybisethane. The product was filtered off and dried, yielding 12.21 parts (86.5%) of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 130.4° C. (interm. 2).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([SH:23])[CH3:22].Cl>CN(C)C=O>[CH2:21]([S:23][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: CCS
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.25 mmol ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid which was used in the next step without further purification (yield 99%). MS (m/e): 259.0 ([M−H]−, 100%).