Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].Cl.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)CCC>[ClH:34].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:4][C:3]3[CH:5]=[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])[C:7]([CH3:9])=[CH:8][C:2]=3[F:1])=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: CCCC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Yield: 94.9 %

Procedure:
2-Fluoro-5-methoxycarbonyloxy-4-methylaniline (883 mg, 4.4 mmol), (prepared as described for the starting material in Example 26), was added to a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (1 g, 3.7 mmol) in 2-pentanol (15 ml) at 120° C. and the mixture was then heated at reflux for 4 hours. The precipitate was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.65 g, 97%/) as a cream solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH:22]=[CH2:23])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH2:22][CH3:23])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
A suspension of trans-2-benzyl-6-chloro-3a-methyl-7-vinyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.095 mmol, 32 mg) and 5% Pd—C (4.74 μmol, 10.08 mg) in MeOH (3 ml) was stirred under H2 atmosphere (1 bar, multiple hydrogenator) at 20° C. for 1.5 h. The suspension was then passed through a Whatman membrane filter and the resulting filtrate was concentrated in vacuo to afford trans-2-benzyl-6-chloro-7-ethyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (24.9 mg), m/z=340.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[Na+:29].[Na+]>CN(C)C=O.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>[NH2:1][C:2]1[C:3]([S:10]([O-:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:14]=[O:15])[CH:21]=1.[Na+:29]
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2cccc(C=O)c2)cc(Br)cc1S(=O)(=O)[O-]
Temperature: 70 °C

Procedure:
A mixture of 11.34 g (30 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid, 4.5 g (30 mmol) of 3-formylbenzeneboronic acid, 10.5 g (99 mmol) of sodium carbonate and 1.73 g (1.5 mmol) of tetrakis(triphenylphosphine)palladium (0) in 40 ml of dimethylformamide and 20 ml of water is heated at 70° C. under argon for 5 hours. The reaction medium is then concentrated under reduced pressure and the residue is purified by chromatography on an RP 18 column, eluting with a water-acetonitrile mixture (8:2).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[Br:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].CS(Cl)(=O)=O.[C-:25]#[N:26].[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[Br:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH2:3][C:25]#[N:26]
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CC#N)c1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To the THF solution (1000 ml) of 2-bromo-5-methoxy-benzoic acid methyl ester (20 g, 81.6 mmol), the THF suspension (50 ml) of LAH (4.07 g, 102 mmol) was added under ice cooling. The mixture was stirred for 30 min under ice cooling. The reaction solution was partitioned between saturated aqueous solution of Na2SO4 and ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting residues were dissolved in DCM (200 ml), and added with TEA (12.51 ml, 89.76 mmol) and MsCl (6.63 ml, 85.68 mmol) under ice cooling, followed by stirring overnight at room temperature. The reaction mixture was diluted with DCM, and washed in order with 10% aqueous solution of citric acid, saturated aqueous solution of NaHCO3 and saturated brine. The residues obtained after concentration under reduced pressure were dissolved in DMF (100 ml), and added with the DMF (500 ml) solution of NaCN (40 g, 81.6 mmol) under ice cooling. After stirring for 2 hrs under ice cooling, the reaction mixture was extracted with ether, washed with saturated brine and dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column (hexane:ethyl acetate=10:1) to obtain the title compound (12.1 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:53][C:54]([NH2:56])=[NH:55]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:55][C:54]([NH2:56])=[NH:53])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(=N)N)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). After stirring for 30 minutes, guanidine carbonate (0.19 g, 1.05 mmol) was added, and the reaction was heated to 100° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification was achieved by preparative HPLC on a Primesphere 5 C18 (0.2×15 cm) column using a solvent gradient from 55:45:0.1 to 90:10:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.25 g of the title compound as a white solid.
Reaction SMILES: CS(C)=O.Br[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][N:14]=2)[N:9]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:8](=[O:30])[C:7]1([CH3:32])[CH3:31].C(=O)([O-])[OH:34].[Na+]>O>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6](=[O:34])[C:7]([CH3:32])([CH3:31])[C:8](=[O:30])[N:9]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(=O)c3ncc(Cl)cc32)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
To a dimethylsulfoxide solution (8 ml) of tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (375 mg) was added sodium hydrogen carbonate (871 mg), followed by stirring at 100° C. for 6 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After the resulting residue was dissolved in dichloromethane (14 ml), manganese dioxide (684 mg) was added and stirred for 50 minutes, and further manganese dioxide (690 mg) was added and stirred for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3,3-dimethyl-2,4-dioxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (270 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[C:17]([Cl:18])[C:12]2=[N:11]1)[C:5]#[N:6].[Br:22][Si](C)(C)C>C(#N)CC>[Br:22][C:14]1[C:13]2=[CH:20][N:10]([C:9]3[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[Cl:21])[N:11]=[C:12]2[C:17]([Cl:18])=[CH:16][N:15]=1
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Cl)ncc(Cl)c3n2)c(Cl)c1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cc(Cl)c(-n2cc3c(Br)ncc(Cl)c3n2)c(Cl)c1
Yield: 96.9 %

Procedure:
A mixture of 3,5-dichloro-4-(4,7-dichloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile (250 mg, 0.70 mmol) and bromotrimethylsilane (0.462 mL, 3.50 mmol) in propionitrile (4.0 mL) was heated under reflux for 4 hours. The resultant mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a beige solid (273 mg, 97% yield). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.16 (s, 1H), 7.85 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][NH:14][C:13]2=[O:25])=[CH:5][CH:4]=1.[N:26]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[NH2:26][N:14]1[CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:12]([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]1=[O:25]
Reactant: COc1ccc(CCCN2C(=O)NCC2c2ccc(OC)cc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CCCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
To a solution of 1-[3-(4-methoxyphenyl)propyl]-5-[(4-methoxy)-phenyl]-2-imidazolidinone (0.6 g, 1.75 mmol) in acetic acid (15 mL) is added dropwise a solution of NaNO2 (0.12 g, 1.8 mmol) in water (1 mL). The mixture is cooled in an ice bath to 5° C. and zinc dust (0.6 g, 9 mmol) is added in portions (starting with 0.5 g addition) over 50 minutes at less than 12° C. The reaction is stirred for 5 minutes and the ice bath is removed. The reaction temperature rises quickly to about 20° C. and the reaction is maintained below about 32° C. with an ice bath. The reaction is stirred for 70 minutes at 20° C. to 27° C. and any unreacted zinc is removed by filtration. The volume of the filtrate is reduced in vacuo then diluted with dichloromethane (15 mL). To the stirred mixture is added concentrated ammonium hydroxide (2 mL), keeping the temperature below about 32° C. with an ice bath. The organic phase is separated, washed with brine, dried (Na2SO4), and concentrated to afford 0.68 g (quantitative yield) of the desired compound as a colorless oil which is used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.ClC1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=[C:26]2[S:35][N:36]=[C:37]([CH3:38])[C:25]=12>CN1CCCC1=O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:4]([CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:3]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=[C:26]3[S:35][N:36]=[C:37]([CH3:38])[C:25]=23)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)N(C)Cc2cccnc2)cc1
Reactant: CCOC(=O)c1cnc2snc(C)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2snc(C)c2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred mixture of 0.366 g (8.4 mmol) of sodium hydride (60% in oil) in 10 ml of dry 1-methyl-2-pyrrolidinone was added (portionwise) 2.34 g (8.4 mmol) of methyl (4-methoxybenzenesulfonyl)pyridin-3-ylmethyl-amine. The mixture was stirred at room temperature until gas evolution ceased and 1.80 g of (7.0 mmol) of ethyl 4-chloro-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate added. The mixture was heated at 80-90° C. for 44 hours, the solvent removed under vacuum and the residue diluted with water. The mixture was extracted with ethyl acetate and the extract washed with 2N citric acid, H2O, 1 N NaHCO3, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the pad washed with ethyl acetate. The filtrate was concentrated to dryness to give 2.39 g of ethyl 4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate as a yellow solid, m.p. 142-144° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][NH:11]/[C:10]/2=[CH:15]\[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH:22]=O>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:10]3=[C:15]([N+:16]([O-:18])=[O:17])[CH:22]4[O:24][CH:19]([N:11]3[CH2:12][CH2:13][CH2:14]2)[CH2:20][CH2:21]4)=[CH:4][CH:3]=1
Reactant: O=CCCC=O
Reactant: O=[N+]([O-])/C=C1\NCCCN1Cc1ccc(Cl)nc1
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCCN2C2CCC1O2
Temperature: 25 °C
Yield: 38 %

Procedure:
To a 50 ml round bottom flask was added 1.34 g (0.005 mol) (E)-1-((6-chloropyridin-3-yl)methyl)-2-(nitromethylene)-hexahydropyrimidine, 30 ml dry acetonitrile and 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated Hl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 38% yield.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:40]=[N:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:48]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cnc3ccccc3c2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 3-aminoquinoline (260 mg, 1.80 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (24 mg, 12% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]([OH:28])=O)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl-].[CH3:30][O:31][NH2+:32][CH3:33].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:30][O:31][N:32]([CH3:33])[C:26]([C:24]1[N:25]=[C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[S:22][CH:23]=1)=[O:28]
Reactant: C[NH2+]OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
At room temperature, triethylamine (324 mg) was added to a suspension of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (1.0 g) in dichloromethane (30 mL). After ten minutes of stirring, methoxy(methyl)ammonium chloride (312 mg), 4-dimethylaminopyridine (39 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide HCl salt (675 mg) were added. The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was separated off and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-{4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.0 g).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[C:7]([CH2:14][CH3:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)(Cl)Cl>[Cl:4][CH:8]([C:7](=[O:6])[CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulphuryl chloride (286 g.) was added dropwise to a solution of ethyl 3-oxopentanoate (300 g.) in chloroform (250 ml.) at 10°-15°. Following addition the mixture was stirred overnight at room temperature, heated under reflux for 0.5 hours and cooled. After washing with water, sodium bicarbonate and water, the solution was dried (sodium sulphate), concentrated, and fractionated to yield ethyl 2-chloro-3-oxopentanoate, b.p. 94°-96°/14 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:10]=[CH:11][C:12]=1[F:13])=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:10]=[CH:11][C:12]=1[F:13])=[O:5]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccc(F)cc3Cl)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccc(F)cc2Cl)c1
Yield: 72.2 %

Procedure:
A mixture of methyl 2-(3-(2-chloro-4-fluorobenzamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.2 mmol), 3.1 mL aqueous solution of sodium hydroxide (124 mg, 3.1 mmol) in 5 mL methanol was stirred at reflux for 1 h. LC-MS indicated that the starting material was consumed completely. The solvent was removed by reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to afford 68 mg of 2-(3-(2-chloro-4-fluorobenzamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a pale yellow solid; yield: 72.3%. MS (ESI+APCI) M+1=471.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]3[C:12](=[O:13])[CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[ClH:23].C(O)(=[O:26])C>>[Cl:22][C:21]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:12]([OH:13])=[O:26])[NH:6][C:5]=2[CH:20]=1.[ClH:23]
Reactant: CC(=O)O
Reactant: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)c(Cl)cc3n21
Agent: Cl
Product: O=C(O)CC(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 7,8-dichloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (96 mg) in a mixture of acetic acid (2 ml) and conc. HCl (1 ml) was heated to reflux shortly and then stirred at rt for 1 h. All volatiles were removed at the water aspirator at elevated temperature and the residue was dried by azeotropic distillation with toluene. The crude was triturated with chloroform (5 ml) to give 4-(5,6-dichloro-2-benzimidazolyl)-3-phenylbutanoic acid•HCl (102 mg) as colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]1([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:37][C:31]1([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)[CH2:32][CH2:33][N:34]([C:22](=[O:24])[CH2:21][O:20][CH2:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][N:13]2[S:10]([C:6]2[C:5]([CH3:25])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:35][CH2:36]1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Reactant: OC1(c2cccs2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCC(O)(c3cccs3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (acid unit S24) (150 mg, 0.404 mmol) in methylene chloride (5 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(thiophen-2-yl)piperidin-4-ol (73 mg, 0.404 mmol) in methylene chloride (2 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/hexane (20:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]([CH:12]1[C:28]2([CH3:29])[CH:15]([CH:16]3[CH:25]([CH2:26][CH2:27]2)[C:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:11])=[O:7].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]([CH:12]1[C:28]2([CH3:29])[CH:15]([CH:16]3[CH:25]([CH2:26][CH2:27]2)[C:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:11])=[O:7])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COC(=O)CCCCBr)CCC12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COC(=O)CCCCN=[N+]=[N-])CCC12
Temperature: 65 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 8 (325 mg, 0.639 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium azide (415 mg, 6.39 mmol). The reaction mixture was heated to 65° C. and stirred overnight. Excess sodium azide was filtered off and the solvent was removed by rotary evaporation. The crude residue was dissolved in ethyl acetate and washed with water three times. The organic layer was dried over sodium sulfate and concentrated followed by flash chromatography in hexanes/ethyl acetate (4:3) to give 10 (206 mg, 71%). 1H NMR (500 MHz, CD3CN) δ 5.62 (1H, s, 4-H), 4.72 (1H, d, J=17, COCH2O), 4.53 (1H, d, J=17, COCH2O), 3.31 (2H, t, J=6.5, CH2N3), 2.55-0.99 (complex, 26H), 1.17 (3H, s, CH3), 0.64 (3H, s, CH3); 13C NMR (125 MHz, CD3CN) δ 204.49, 199.18, 173.04, 171.81, 123.86, 69.81, 59.25, 56.55, 54.21, 51.43, 44.95, 39.12, 38.60, 36.20, 35.94, 34.28, 33.36, 32.96, 32.52, 28.46, 24.79, 23.62, 23.07, 21.46, 17.35, 13.20. ESI-MS m/z [M+Na]+ observed: 478.3, calculated: 478.3.