Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[CH2:8][CH2:9][N:10]([CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16].O.[OH-].[Na+]>CO>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:9][CH2:8][C:7]1[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=1[O:5][CH2:4][C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[Cl:1])([OH:17])=[O:16]
Reactant: COC(=O)CCCCN(CCc1ccccc1OCc1ccccc1Cl)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCN(CCc1ccccc1OCc1ccccc1Cl)Cc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
124.8 mg (0.238 mmol) of methyl 4-{[{2-[(2-chlorobenzyl)-oxy]phenethyl}(5-methoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 1 are initially charged in 0.3 ml of methanol and 0.17 ml of water and admixed with 0.2 ml of a 40% strength sodium hydroxide solution. The mixture is stirred at 60° C. for one hour and then cooled, and the methanol is distilled off under reduced pressure. The aqueous phase is adjusted to pH 4 by addition of a citric acid/aqueous sodium hydroxide solution buffer and the resulting precipitate is separated off. Tituration with boiling cyclohexane gives a finely crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: COC(=O)c1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(C)nccn32)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@H](c2nc(Br)c3c(C)nccn32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (cis)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (46.8 mmol, 12.8 g) in N,N-dimethylformamide (100 ml) was added N-bromosuccinimide (46.8 mmol, 8.33 g). After stirring at room temperature for one hour the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic layers were washed with water twice, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 3% of methanol) to give (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (15.34 g).
Reaction SMILES: S(=[N:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[CH2:27][CH3:28])=[O:8])=O.Cl>ClCCl.O1CCCC1>[NH2:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:19])([F:20])[F:21])=[CH:12][C:11]=1[CH2:27][CH3:28])=[O:8]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-sulfinylamino-N-[2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.111 g, 0.237 mmol) (for example, Example 2.1) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was treated with aqueous hydrochloric acid (2N) (1 ml) and stirred at 25° C. for 30 minutes. The organic solvents were removed from the reaction mixture under reduced pressure. The residue was neutralized with aqueous sodium hydrogen carbonate (saturated) and was extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to yield the desired compound. 1H-NMR (CDCl3, 400 MHz): 7.44 (s, 1H), 7.38 (s, 2H), 7.30-7.20 (m, 3H), 6.89 (d, 1H), 3.85 (bs, 2H), 2.69 (q, 2H), 2.32 (s, 3H), 1.22 (t, 3H) ppm.
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:63])[C:50](Br)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:63])[C:50]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.922 mmol) in DMF (3 mL) was added sodium hydride (37 mg, 60% in oil, 0.925 mmol). The mixture was stirred at RT for 15 min, then a solution of 2-bromo-2-phenylmalonic acid diethyl ester (435 mg, 1.38 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at RT for 30 min, and then at 90° C. for 2 h. The cooled reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording the title compound as a colourless gum (0.3933 g, 76%). LCMS (Method J): RT 3.73 min [M+H]+ 560
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:15])=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2c1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
30 Milliliters of anhydrous pyridine and 10 ml of DMF were added to 1.8 g of 4-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.7 g of DCC and 130.9 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was collected by filtration and washed with a small amount of DMF. To this collected precipitate was added 100 ml of DMF, to dissolve the precipitate with heating, followed by stirring for 2 hours under cooling with ice. Then, insoluble matter was filtered off and the filtrate was concentrated to 20 ml under reduced pressure. The residue was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. The residue was suspended with addition of 20 ml of methanol and 0.6 ml of concentrated hydrochloric acid, and the suspension was added dropwise to a mixed liquid of 200 ml of ether and 20 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.35 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-nitrobenzoate.hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:17])[F:19])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1ccc(-c2ccccc2C(F)(F)F)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccccc2C(F)(F)F)ccc1CBr

Procedure:
A mixture of 3-cyano-4-methyl-2'-trifluoromethylbiphenyl (420 mg, 1.61 mmol), N-bromosuccinimide (286 mg, 1.61 mmol), AIBN (10 mg), and carbon tetrachloride (20 mL) was refluxed for 1 hour. The resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate in hexane (7.5 to 92.5 v/v). Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(OC)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(OC)cc(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 87.7 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methoxybenzoate obtained in Example (257c) (about 0.25 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (48 mg, 0.22 mmol), WSC hydrochloride (139 mg, 0.73 mmol), HOBT (49 mg, 0.36 mmol), dichloromethane (2 mL) and DMA (2 mL), to obtain 87 mg of the title compound (88%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C@@H:20]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=2)[CH3:21])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:29][C:25]1[N:24]=[C:23]([NH:22][C@H:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:1]=[CH:2][NH:3][C:4]=4[CH:9]=3)=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH3:21])[CH:28]=[N:27][CH:26]=1
Reactant: O=C(Cl)c1ccc2nc[nH]c2c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2ccc3nc[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-benzimidazole carbonyl chloride (108 mg, 0.5 mmol), (S)—N-(1-(3-aminophenyl)ethyl)-6-chloropyrazin-2-amine (144 mg, 0.5 mmol) and triethylamine (0.7 mL, 5 mmol) was stirred at room temperature for 72 hours. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium hydrogen carbonate (2×15 mL), brine (15 mL), dried (MgSO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-1H-benzo[d]imidazole-6-carboxamide as a yellow powder.
Reaction SMILES: [BH4-].[Na+].Br[CH2:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)=[O:6].O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])=[CH:21][CH:20]=1>CO>[OH:6][CH:5]([C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)[CH2:4][N:28]([CH:26]([CH3:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)s1
Reactant: COc1ccc(CC(C)NCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)CN(Cc2ccccc2)C(C)Cc2ccc(OC)cc2)s1
Temperature: 0 °C

Procedure:
Sodium borohydride (3.14 g) was added to an ice-cold suspension of methyl 5-(bromoacetyl)thiophene-2-carboxylate (4.14 g) in methanol (250 ml). After 15 min the reaction mixture was poured into iced water (1000 ml) and extracted with ethyl acetate (5×200 ml). The dried (MgSO4) organic phase was evaporated to give a yellow oil, which was heted with [2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amine (5.18 g) at 100° for 16 h. The cooled reaction mixture was partitioned between water (400 ml) and ethyl acetate (3×400 ml), and the dried (MgSO4) organic phase was evaporated, giving the crude product as an oily brown solid (9.75 g). This was applied on silica to a short-path silica column (1000 g) eluted with cyclohexane 15% diethyl ether. The appropriate fractions (Rf 0.15) were combined and evaporated to give the ethanolamine (slightly impure) as an oily beige solid (2.4 g). TLC SiO2 (Et2O/cyclohexane, 1:1 ) Rf 0.39.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 0.133 mmol) was reacted with the product from Example 4c (231 mg, 0.133 mol) for 5 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (288 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 2H) 1.85 (m, 2H) 2.33 (s, 3H) 3.00 (t, J=7.35 Hz 2H) 6.29 (d, J=6.99 Hz, 1H) 6.73 (d, J=8.46 Hz, 2H) 7.00 (m, 2H) 7.19 (d, J=8.46 Hz, 2H) 7.27 (s, 1H) 7.83 (d, J=8.82 Hz, 1H) 8.43 (d, J=7.35 Hz, 1H) 9.04 (d, J=8.46 Hz, 1H) 9.90 (s, 1H) 11.04 (s, 1H) 14.40 (br. s, 1H); MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[FH:17].[FH:18].F.C(N(CC)CC)C>C(Cl)Cl>[F:17][C:11]1([F:18])[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:15]#[N:16])[CH2:9][CH2:10]1
Reactant: N#CC1(c2ccc(F)nc2)CCC(=O)CC1
Reactant: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1(c2ccc(F)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred suspension of diethylamino difluorosulfiinium tetrafluoroborate salt (23.8 g, 0.104 mol) in dry DCM (100 mL) at room temperature was added 1-(6-fluoro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (12 g, 0.052 mol) followed by triethylamine trihydrofluoride (25.12 g, 0.156 mol) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The resulting mixture was then quenched with saturated aq. NaHCO3 solution (300 mL), stirred for 10 minutes, and the resulting mixture was extracted with DCM (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with a gradient elution of between 2-10% EtOAc in petroleum ether) to afford the title compound (8 g, yield: 64%). 1H NMR (CDCl3 400 MHz): 6 ppm 8.40-8.35 (m, 1H), 7.95-7.84 (m, 1H), 7.05-6.96 (m, 1H), 2.40-2.10 (m, 8H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:19]([CH:21]=O)=O>C(#N)C>[N:10]12[CH:21]3[N:7]([CH2:6][CH2:5][N:4]4[CH:19]3[N:1]([CH2:12][CH2:11]1)[CH2:2][CH2:3]4)[CH2:8][CH2:9]2
Reactant: O=CC=O
Reactant: CCNCCNCCNCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C1CN2CCN3CCN4CCN1C2C43

Procedure:
1,4,7,10-Tetraazadodecane (1.1.4) trihydrobromide in acetonitrile with potassium carbonate was reacted with glyoxal to form 1,4,7,10-tetraazatetracyclo-[5,5,2,04,13,010,14] tetradecane (1.1.23). Following separation the pure product was obtained by low pressure distillation. This was dissolved in acetonitrile and benzylbromide was added to form 1,7-dibenzylonium-1,4,7,10-tetraaza-tetracyclo[5,5,2,04,13,010,14] tetradecane (1.1.24). Following recrystallization from ethanol this was reacted with sodium borohydride. HCl was added, followed by water and NaOH, and the product extracted with chloroform. Following evaporation of solvent the solids were dissolved in methanol and HBr was added to obtain 1,7-dibenzyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane (1.1.25) as the hydrobromide salt. This was dissolved in water and reduced using H2 and a Pd-C catalyst to remove the benzyl groups. Purification of the title compound was by crystallization of the hydrobromide salt. The base form was obtained by low pressure distillation following addition of base. 1.1.26 1,4,7,10,13-Pentaazabicyclo [8.5.2] heptadecane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:11][CH2:10][C:9]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:8][CH2:7]1)[CH2:14][C:13]2=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2=O
Temperature: 25 °C

Procedure:
Toluene (100 mL) was added to 1-acetyl-4-oxocyclohexyl carboxylic acid ethyl ester (8.0 g, 38 mmol) and then the resulting mixture was stirred. To the mixture, there were added benzylamine (5.3 mL, 49 mmol) and p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol). The mixture was refluxed for 8 hours with a Dean-Stark apparatus under the dehydration conditions. After cooled to room temperature, the mixture was concentrated under reduced pressure to give a crude product. The resulting crude product was treated according to the silica gel column chromatography (eluting solution: hexane/ethyl acetate) to thus obtain a mixture of the desired product and an imine derivative thereof. The mixture was dissolved in chloroform (200 mL) and then the resulting solution was treated with a 0.5 mol/L hydrochloric acid solution (100 mL). The suspended organic phase was separated, then treated with a 5% aqueous solution of sodium hydrogen carbonate and then separated. The organic phase was dried over anhydrous magnesium sulfate, followed by the removal of the drying agent through filtration and the subsequent concentration of the resulting filtrate under reduced pressure to thus give the desired product as a white solid. (2.9 g; yield: 26%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([F:11])[C:5]2=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]c(Cl)nc(Cl)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Reaction time: 24 h

Procedure:
A solution of 2,4-dichloro-5-fluoro-1H-pyrrolo[2,3-d]pyrimidine (1.65 g, 8.01 mmol, crude material from abovefl) in dichloromethane (100 ml) was treated with DIPEA (2.80 ml, 16.02 mmol) and p-toluenesulfonylchoride (1.756 g, 9.21 mmol) and stirred for 24 hours. The mixture was poured into saturated sodium bicarbonate/DCM and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography (10% EtOAc/Hex). The chromatographic residue (still containing multiple impurities) was further purified with a 65% isocratic MeCN mobile phase on a Luna C18 5 um, 21×150mm column, 20 mL/min, UV @275 nm. The final purity of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine was estimated at 99.5% at 254 nm using the same method (1.128 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=2.20 Hz, 1H), 7.96 (d, J=8.24 Hz, 2H), 7.47 (d, J=8.79 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:25][O:24][C:23]1[C:3]([O:2][CH3:1])=[C:4]2[C:20]([CH:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[CH2:7][NH:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3c2ccc(OC)c3OC)cc1OC
Yield: 79.1 %

Procedure:
1.0 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 7.5 ml of trifluoroacetic acid, and after adding thereto 0.23 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding to the mixture chloroform, the mixture was basified by addition of 28% aqueous ammonia under ice cooling. After a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue thus obtained was recrystallized from chloroform-n-hexane, affording 750 mg of 7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (m.p. 109°-110° C.).