Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.431 g (5.0 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.70 g (87.4%, yellow oily substance) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=4)[C:15](=[O:26])[CH:14]=3)[CH:10]=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([C:29]#[N:30])[N:20]=4)[C:15](=[O:26])[CH:14]=3)[CH:10]=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(Cn2cncc2Oc2ccc(Br)cc2)ccn1-c1cncc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cncc(-n2ccc(Cn3cncc3Oc3ccc(Br)cc3)cc2=O)n1

Procedure:
A mixture of 4-[5-(4-Bromophenoxy)imidazol-1-ylmethyl]-1-(6-chloropyrazin-2-yl)-1H-pyridin-2-one (79 mg, 0.17 mmol) and zinc cyanide (12 mg, 0.1 mmol) in DMF (1 mL) was purged with argon for 5 min. A solution of tetrakis(triphenylphosphine)palladium(0) (20 mg, 17 μmol) in DMF (0.5 mL) was added. The resultant mixture was stirred under argon at 80° C. overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection, concentration of appropriate fractions, and trituration of the residue with anhydrous ether provided the titled compound as white solid.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:6][CH2:5]1)=[O:3].[CH3:17][O:18]C1C=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:17])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)Cl)CC1
Yield: 57 %

Procedure:
Compound 39A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(o-methoxyphenyl)piperazine (441 mg, 2.3 mmol); triphosgene (210 mg, 0.7 mmol); triethylamine (315 ml, 2.3 mmol); tetrahydrofuran (30 ml).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2F)CCC1

Procedure:
using isopropyl 2,4-difluoro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2,4-difluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 149°-151° C.,
Reaction SMILES: [NH:1]([CH:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=1)[CH3:4])[OH:2].C[Si]([N:23]=[C:24]=[O:25])(C)C.O>O1CCCC1>[CH:6]1[C:7]2[S:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][C:5]=1[CH:3]([N:1]([OH:2])[C:24]([NH2:23])=[O:25])[CH3:4]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(NO)c1ccc2c(c1)Sc1ccccc1O2
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)Sc1ccccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 2 (250 mg, 0.965 mmol) in tetrahydrofuran (THF, 4 mL) there was added 85% trimethylsilyl isocyanate (196 mg, 1.45 mmol) and the solution was stirred at room temperature for 1 hour. Water (4 mL) was added, stirring was continued for 10 minutes, then the THF was evaporated; the residue was extracted twice with ether and the crude product obtained from evaporation of the extracts was crystallized from ether to afford the title compound as white crystals, m.p.: dec 155° C. with gassing.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(#N)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Yield: 46 %

Procedure:
30.3 g of (2R/S,5S/R)-tert-butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate was applied to chiral column chromatography (CHRAL PAK IA, methanol/acetonitrile=95/5), and the active fraction corresponding to the first peak was collected to afford 13.9 g of the title compound as a colorless solid (yield 46%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 4.2 min.). Mp 84° C.; [α]20D−6.1° (c 0.83, CHCl3); 1H NMR and MS were equivalent to those of the title compound of Example 6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Clc1ccc(C2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.81 g), triethylamine (1.4 cc) and 4-(4-chlorophenyl)piperidine (1.96 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization firstly from boiling acetonitrile (12 cc) and then from boiling acetonitrile (17 cc), 2-{3-[4-(4-chlorophenyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 111° C.
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH3:15])[CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1.CO>[CH3:15][C:7]1[CH:6]=[C:5]([OH:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)Oc1cc(C)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)c2c(c1)CCCC2
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixed solution of 3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate synthesized in Reference Example 173 (5.1 g, 25.1 mmol) in THF (120 mL) and methanol (30 mL) was added 12 N aqueous sodium hydroxide solution (2.5 mL) at room temperature, and the mixture was stirred for 30 minutes, and then concentrated under reduced pressure. Water and hydrochloric acid were added to the residue, and the mixture was acidified, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized with ethyl acetate-hexane to obtain 4.1 g (yield 99%) of the title compound. Melting point: 95-96° C. (hexane-ethyl acetate).
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([OH:46])=O)[CH2:41][O:42][C:37]=2[CH:36]=1.[NH4+].[Cl-].CCOC(C)=O>C(Cl)Cl>[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([NH2:4])=[O:46])[CH2:41][O:42][C:37]=2[CH:36]=1
Reactant: O=C(O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
PyBOP (127 mg, 0.24 mmol) and TEA (0.141 mL, 1.02 mmol) was added to a solution of {(3S)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 22a, 82 mg, 0.20 mmol) in DCM (2 mL). Thereafter, NH4Cl (43.6 mg, 0.81 mmol) was added and the mixture was stirred at rt for 1.5 h. EtOAc (30 mL) was added and the mixture was washed with sat. aq. Na2CO3 (30 mL), HCl (0.5M, 20 mL) and brine (20 mL). The product was purified by preparative HPLC (Phenomenex Luna Hilic column (5 μm 250×30 ID mm) using a gradient of 10 to 45% MeOH/DEA 100/0.5 in CO2, 120 bar, over 6 min at 40 OC) to give the title compound (42.0 mg, 51.3%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+]>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC/C=C/CCc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC/C=C/CCc1ccc(-c2ccccc2)cc1

Procedure:
Ethyl E-7-((4-phenyl)phenyl)hept-4-enoate was saponified in methanolic sodium hydroxide at room temperature. The resulting acid, E-7-((4-phenyl)phenyl)hept-4-enoic acid, was obtained in >95% purity after chromatography. The product was fully characterized by spectral analysis infrared and nuclear magnetic spectroscopy) and combustion analysis.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[N:23]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Commercially available 3-(chlorosulfonyl)benzoic acid (3 g, 13.5 mmol) was suspended in dichloromethane (50 mL). Diisopropylethylamine (5.19 mL, 30 mmol) and morpholine (1.67 mL, 21 mmol) were added slowly. After 2 h, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 3N HCl three times. The ethyl acetate phase was dried over magnesium sulfate and the solvent was removed under reduced pressure, to provide the title product (2.97 g, 81%) as a white solid. 1HNMR (DMSO-d6) δ8.28 (d, J=8 Hz, 1H), 8.20 (s, 1H), 8.01 (d, 8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 3.91(m, 4H), 3.12 (M, 4H). MS (EI-NEG):[M+] 270.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)=[O:12]>>[F:28][C:27]([F:30])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:11](=[O:12])[N:4]([C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[CH3:5])=[CH:15][CH:16]=2)=[N:22][CH:23]=1
Reactant: CNc1ccccc1Cl
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1Cl

Procedure:
The title product was prepared from 2-chlor-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (48%, light yellow oil). HPLC-MS m/z=423.1 (M+1), Rt: 4.98 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccncc1
Product: N#CCc1nc(-c2ccncc2)cs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-bromo-1-(pyridin-4-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.23 g, yield 46%): 1H NMR (300 MHz, MeOD) δ 8.59 (m, 2H), 8.24 (s, 1H), 7.98 (m, 2H), 4.44 (s, 2H). MS (ESI) m/z: Calculated for C10H7N3OS: 201.01. found: 202.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][C@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:60]2[CH2:61][CH2:62][CH2:63][C@H:59]2[CH2:58][O:57][CH3:56])=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: COC[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1C(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (R)-(-)-2-(methoxymethyl)pyrrolidine (46 mg, 2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:14]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[OH:38]O>C(O)(=O)C.C([O-])(=O)C>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][CH2:20]3)[C:14]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:13]=3[N:12]=2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCN1CCSCC1
Reactant: OO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCN1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.2 g of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-(3-thiomorpholino-propyl)-benzimidazole-hydrochloride are dissolved in 45 ml of glacial acetic acid and a solution of 0.39 ml of 30% hydrogen peroxide in 5 ml of glacial acetate acid is added thereto whilst cooling with ice water. The mixture is stirred for 4 hours whilst cooling with ice and for 16 hours at ambient temperature, the solvent is evaporated off in vacuo and the residue is purified by column chromatography (silica gel; methylene chloride/methanol/water=1:1:0 to 1:1:0.1). Yield: 0.6 g (26% of theory), Rf value: 0.46 (silica gel; methylene chloride/methanol/conc. ammonia=1:1:0.1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([C:16]2[CH2:17][CH2:18][N:13]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cccc(C2=CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1

Procedure:
The reaction of tert-butyl N-(3-bromopropyl)carbamate and N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide in refluxing dioxane with catalytic Bu4NI and base as described in Scheme A gave tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11-12) gave the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[N:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cnnc(N2CCNCC2)c1
Reaction time: 0.5 h

Procedure:
4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (45 mg) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid was added (0.5 mL). The reaction mixture was stirred for 30 minutes before being concentrated in vacuo to afford the crude title compound which was used directly in the next step without further purification or analysis.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH2:51])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH:51][C:7]([C:5]3[N:4]=[CH:3][C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=3)=[O:9])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cnc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)cn1
Reaction time: 5 h

Procedure:
Pyrazine-2,5-dicarboxylic acid (0.58 g; 3.42 mmol), anhydrous HOBt (0.69 g; 5.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) were added to 5 ml of DCM. 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (1.0 g; 3.42 mmol) and DIPEA (0.89 ml; 5.13 mmol) were dissolved in 5 ml of DCM and added dropwise to the previous mixture. The reaction mixture was stirred overnight after which pyrazine-2,5-dicarboxylic acid (0.58 g; 1.59 mmol) and DIPEA (0.60 ml; 3.42 mmol) were added and the mixture was again stirred for 5 h. Anhydrous HOBt (0.69 g; 5.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) and DIPEA (0.89 ml; 5.13 mmol) were again added to drive the reaction to completion. After overnight stirring the mixture was diluted with 20 ml of DCM and washed with 3×10 ml water. The organic phase was dried over Na2SO4, filtered and used as such without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:13][N:14]2[CH:23]=[C:22]([S:24][CH2:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:39]4[CH:44]=[C:43]([C:45](=[O:50])[NH:46][CH:47]5[CH2:49][CH2:48]5)[CH:42]=[C:41]([F:51])[C:40]=4[CH3:52])[CH:20]=3)[C:15]2=[O:53])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.C(O)C>Cl.O1CCOCC1>[CH:47]1([NH:46][C:45](=[O:50])[C:43]2[CH:44]=[C:39]([C:19]3[CH:20]=[C:21]4[C:16](=[CH:17][CH:18]=3)[C:15](=[O:53])[N:14]([CH2:13][C:10]3([CH2:9][OH:8])[CH2:12][CH2:11]3)[CH:23]=[C:22]4[S:24][CH2:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[C:40]([CH3:52])=[C:41]([F:51])[CH:42]=2)[CH2:49][CH2:48]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CC3)cc(SC[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO)CC3)cc(SC[C@@H]3CCCNC3)c2c1
Yield: 79.6 %

Procedure:
A solution of tert-Butyl (3R)-3-{[(2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}piperidine-1-carboxylate (Example 63e, 110 mg) in 4N HCl in dioxane (1 mL) and ethanol (3 mL) was stirred for 20 h before being concentrated in vacuo. The residue was dissolved in methanol (2 mL) and loaded onto a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1N methanolic ammonia (50 mL) and evaporated in vacuo to afford the title product (63 mg) as a white solid.