Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[N:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[S:4][CH:3]=2)=[CH:14][CH:15]=1
Reactant: Nc1csc2cnccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: c1cc(Nc2csc3cnccc23)ccn1
Temperature: 0 °C
Yield: 26.4 %

Procedure:
A solution of 3-aminothieno[2,3-c]pyridine (10 g) and 4-chloropyridine hydrochloride (10 g) in 200 mL of 1-methyl-2-pyrrolidinone was stirred at 80° C. for four hours, and then was cooled, stirred with ice-water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and then was dried (an hydrous magnesium sulfate), filtered and evaporated. Gradient elution through silica with dichloromethane followed by 10% methanol in dichloromethane afforded 4 g (26%) of a tan solid, m.p. 236°-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:31])([F:43])[F:44])=[CH:34][CH:35]=4)[CH2:41][CH2:40]3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)NC3(c4ccc(C(F)(F)F)cc4)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 10.1 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-37, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.38 (d, J=9.0 Hz, 4H), 1.52 (s, 6H), 3.07 (s, 2H), 7.32-7.35 (m, 6H), 7.61-7.64 (m, 2H), 8.39 (s, 1H), 9.20 (s, 1H), 11.0 (s, 1H); MS [M+H]+: 559.25.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)C.[OH-].[Na+]>O>[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[O:6][CH2:5][C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)COc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1nc2ccccc2o1
Yield: 31.1 %

Procedure:
The solution of 0.2 g (0.9 mmol) ethyl-(1,3-benzoxazol-2-yloxy)acetate and 0.4 g (1 mmol) sodium hydroxide in 1 ml water is stirred for 2 hours at room temperature, then extracted with 3×5 ml chloroform. The united organic phase is dried over sodium sulfate and evaporated in vacuum to obtain 54 mg title compound as an oil. LC-MS[MH+]=194 (C9H7NO4 193.16)
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([C:9]([O:11]CC)=[O:10])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[CH:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cnc(C(=O)O)s1

Procedure:
A solution of ethyl 5-isopropylthiazole-2-carboxylate (example 54, step a) (0.105 g) in methanol (5 mL) was treated with a solution of lithium hydroxide (0.025 g) in water (3 mL) and the resultant mixture was stirred vigorously at 20° C. for 2 hours. The methanol was evaporated off under reduced pressure and the residual aqueous solution was diluted with brine (10 mL). The aqueous layer was washed with ether, then cooled in an ice bath and acidified by dropwise addition of concentrated aqueous hydrochloric acid. The mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.048 g.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:20][CH2:21]OCC>C(O)(=O)C>[CH3:14][N:4]1[C:3](=[O:15])[C:2]2[NH:1][C:20]([CH3:21])=[N:8][C:7]=2[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:5]1=[O:13]
Reactant: CC(O)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)c(=O)n(C)c(=O)n2CC(C)O

Procedure:
16 g (0.075 mol) of 5,6-diamino-1-(2-hydroxypropyl)-3-methyl-2,4-(1H, 3H)-pyrimidinedione (VI) was refluxed in 35 ml of acetic acid for 15 minutes. To the warm solution 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 16 g (VII). These crystals were refluxed in 40 ml of 2 N NaOH for 30 minutes and then neutralized with 18 ml of 5 N hydrochloric acid. Crystals were filtered off and recrystallized from 50 ml of water. Yield 6.6 g (VIII). NMR.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.O>C1(SC)C=CC=CC=1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][CH:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a room temperature, stirred mixture of (S)-3-(4-benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid (0.033 g, 0.000058 mol) in thioanisole (0.34 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and rotary-evaporated under reduced pressure to remove volatiles. The resulting yellow solution was chromatographed on silica gel (5.5 g) eluting with dichloromethane (10×5 mL) followed by dichloromethane-methanol (14:1). Fractions containing product were rotary-evaporated. The residue was suspended in water and stirred to give the title compound as an off-white solid; yield 0.0079 g (28%), mp=108-110° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:13][C:12]([CH2:25][CH3:26])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH2:25][CH3:26])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
A solution of 287 mg (0.54 mmol, 70% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-ethyl-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 167A) in 5.5 ml of 1,4-dioxane was admixed with 2.7 ml of aqueous 2M sodium hydroxide solution. The mixture was stirred at 90° C. for a further 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was admixed with water and the pH was adjusted to 7. The resulting precipitate was filtered off and dried under reduced pressure, which gave 280 mg (35% yield, 23% purity) of product, which were used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]1[S:17][C:18]([F:21])=[CH:19][N:20]=1)(=[O:14])=[O:13])[CH2:7]2.[N:22]1([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2C2C=CC=C3C=2CNCC3)[CH:26]=[CH:25][N:24]=[CH:23]1.Cl.BrC1C=CC=C2C=1CCNC2>>[N:22]1([C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=2[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]2[S:17][C:18]([F:21])=[CH:19][N:20]=2)(=[O:14])=[O:13])[CH2:7]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(Br)cccc2C1
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CNCC3)c(-n2ccnc2)c1
Agent: Brc1cccc2c1CCNC2
Agent: Cl
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2-n2ccnc2)C1

Procedure:
The title compound was prepared in a procedure analogous to Intermediate I, wherein 8-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate R) was substituted for 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride [M+H]+=524.0 1H NMR (400 MHZ, Acetone-d6) δ ppm: 7.97 (s, 1H), 7.91 (dd, J=7.9, 1.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.44 (t, J=1.3 Hz, 1H), 7.10-7.19 (m, 2H), 6.97-7.02 (m, 3H), 4.28-4.41 (m, 2H), 3.68-3.77 (m, 1H), 3.21-3.32 (m, 1H), 2.44-2.54 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester as a light yellow oil, MS: 391 (M, 1Cl).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.C(N(CC)CC)C.CS(Cl)(=O)=O.[H-].[Na+].[Cl:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][C:59]=1[NH:60][CH3:61])[C:55]#[N:56].[NH4+].[OH-]>C(Cl)Cl.CN(C)C=O.O>[Cl:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][C:59]=1[N:60]([C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]1[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1)[CH3:61])[C:55]#[N:56]
Reactant: CNc1ccc(C#N)cc1Cl
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C#N)cc2Cl)C1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 61 %

Procedure:
To a stirred solution of the mixture of 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol (251 mg, 1.00 mmol) and triethylamine (0.167 ml, 1.20 mmol) in CH2Cl2 (4 ml) was added methanesulfonyl chloride (0.093 ml, 1.20 mmol) dropwise at 0° C. (ice bath). After 15.5 h stirring at room temperature, the reaction mixture was washed with saturated NaHCO3 aqueous solution, brine, dried (Na2SO4), and concentrated to give 238 mg of brown viscous oil-(i). To a suspension of NaH (48 mg, 1.20 mmol) in N,N-dimethylformamide (2 ml) was added a solution of 3-chloro-4-methylaminobenzonitrile (200 mg, 1.20 mmol) at room temperature. After stirring for 45 min, to this mixture was added a solution of the above brown viscous oil-(i) in N,N-dimethylformamide (2 ml) at room temperature and the mixture was stirred at room temperature for 4.5 h. H2O was added to this mixture, basified with 25%-NH4OH and extracted with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel 20 g, CH2Cl2/MeOH: 100/1-50/1) to afford 244 mg (61%) of brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])C(OCC)=O)[CH3:2].O=P1(C)CCC=C1.[Cl-].[Na+]>O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)(C(C)C)C(C)C
Agent: CP1(=O)C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C(C)C)C(C)C
Yield: 68.1 %

Procedure:
16.9 g (0.069 mol) of diisopropyl-malonic acid diethyl ester (prepared according to J. Chem. Soc., 1931, page 2,336), 25 ml of 1-oxo-1-methyl-phospholine, 4.5 g of sodium chloride and 3.2 g of water were heated to 160°-170° C. for 14 hours. After cooling, the mixture was diluted with 200 ml of water and extracted by shaking four times with a total of 200 ml of petroleum ether and the petroleum ether phase was washed twice with 50 ml of water each time and dried with sodium sulphate. After distilling off the petroleum ether under normal pressure, the crude product was fractionally distilled in vacuo. 8.1 g (68% of theory) of diisopropylacetic acid ethyl ester of boiling point 70°-72°/22 mm Hg were obtained (refractive index nD22 =1.4160).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1.Cl.CC(=O)OCC>CC(=O)OCC>[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ncc2c1CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a stirred mixture of tert-butyl 1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (744 mg, 3.14 mmol) in EA (2 mL) was added HCl/EA (3N, 4 mL). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was then concentrated and the residue purified by Prep-HPLC and SFC to afford the target compound as colorless oil which was used without further purification in the next step. (120 mg; yield 28%). LCMS (m/z): 138.10 (M+1).
Reaction SMILES: C1(C)C=CC(C(C(C(O)=O)(O)C(C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[CH2:39][CH:38]([NH:41]CC1C=CC=CC=1)[CH2:37][CH2:36]2>>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]2
Reactant: COc1cccc2c1CC(NCc1ccccc1)CC2
Agent: Cc1ccc(C(=O)C(O)(C(=O)O)C(O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Product: COc1cccc2c1CC(N)CC2

Procedure:
The resolution is performed on 8-methoxy-2-(benzylamino)tetralin with the aid of (-)-di-p-toluoyltartaric acid according to Karlsson, et al., Acta Chem. Scand., B 42, 231-236 (1988). The enantiomers of 8-methoxy-2-(benzylamino)tetralin are debenzylated, yielding the corresponding enantiomers of 8-methoxy-2-aminotetralin, i.e., R-(+)- and S-(-)-8-methoxy-2-aminotetralin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C=O.Cl[CH:33](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][N:19]([CH3:33])[C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)-4-(methylsulfonyl)aniline (6 mg, 0.014 mmol) from Example 7 and paraformaldehyde were added to dichloroethane (0.2 mL), then sodium triacetoxyborohydride (10.1 mg, 0.041 mmol) was added and stirred overnight at room temperature. The reaction was quenched with sodium bicarbonate saturated solution (10 mL), extracted with EtOAc (10 mL), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 50% ethyl acetate/hexane to give the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[CH2:7]2>Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C@@:3]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[CH2:7]2
Reactant: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-aminomethyl-3-sec-butylbicyclo[3.2.0]hept-3-en-6-yl]acetate (2.26 g, 7.7 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (30 mL), and the solution was stirred at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane to obtain the compound of interest as a white powder (0.98 g, 54%).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:20])=[O:15]
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C(=O)OCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 2-methylpropanoate (518 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 4 (397 mg, 66% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.95 (br. m, 2H), 1.08 (d, J=7.2 Hz, 6H), 1.17-1.39 (br. m, 3H), 1.64-1.73 (br. m, 2H), 1.82-1.91 (br. m, 2H), 2.10 (tt, J=11.8, 3.8 Hz, 1H), 2.55 (hept., J=7.2 Hz, 1H), 2.78-2.88 (br. m, 2H), 5.61 (s, 2H), 7.55 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 302.09 (M+H)+; 299.99 (M−H)−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:12]([NH:13][C:14](=O)[CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:11][N:10]=[C:9]1[C:33](OC)=[O:34].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:7][N:8]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:11][N:10]=[C:9]1[CH2:33][OH:34]
Reactant: COC(=O)c1nnc(NC(=O)CCCOc2cccc(CN3CCCCC3)c2)n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(CO)nnc1NCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 7.7 %

Procedure:
Lithium aluminium hydride (0.46 g) was added to a solution or methyl 4-methyl-5-[[1-oxo-4[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-4H-1,2,4-triazole-3-carboxylate (0.58 g) in dry tetrahydrofuran (20 ml) under an atmosphere of dry nitrogen. The grey suspension was stirred at room temperature for 3.5 h before adding water (0.5 ml), 15% aqueous sodium hydroxide (1.0 ml), water (0.5 ml) and ethyl acetate (20 ml). The suspension was filtered and the filtrate was evaporated under reduced pressure to give a solid which was recrystallised from ethyl acetate (5 ml) to give the title compound as a white solid (0.04 g) m.p. 128°-30°.
Reaction SMILES: B(F)(F)F.[CH2:5]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][C:22]=1[CH:30]=[CH:31][C:32](OCC)=[O:33])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[CH2:5]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][C:22]=1[CH:30]=[CH:31][CH2:32][OH:33])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C=Cc1oc2ccccc2c1CC1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCC1Cc1c(C=CCO)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
At −78° C., BF3.etherate (0.6 mL, 4.8 mmol) was added to a solution containing 47 (1.7 g, 3.9 mmol) in anhydrous DCM (40 mL). After 10 min, DIBAL (1 M/DCM, 10 mL, 10 mmol) was added dropwise from an addition funnel. After 5 min following the complete addition of the DIBAL solution, EtOAc (10 mL) was added to quench the excess reagent. Dilute aqueous HCl was slowly added and the reaction mixture was allowed to slowly warm to ambient temperature. The product was extracted with DCM and EtOAc and the combined organic extracts were washed with dilute aqueous HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (EtOAc/hexane, 1:2) to afford 1.1 g (72%) of 60 as a yellow-colored oil. 1H NMR (CDCl3, 300 MHz) δ7.65 & 7.03 (rotamer, d and app t, J=6.9, 7.8 Hz, 1H), 7.38 (m, 5H), 7.26-7.19 (m, 2H), 6.70-6.52 (m, 2H), 5.26-5.14 (m, 2H), 4.38 (m, 1H), 4.28 (m, 1H), 4.14 (m, 1H), 3.43 (m, 2H), 3.27 & 3.02 (rotamer, 2 m, 1H), 2.76-2.68 (m, 1H), 2.45 (m, 1H), 1.77-1.68 (m, 5H) ppm.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:28][O:29][CH2:30][CH3:31])[N:15]([CH2:16][C:17]([NH:20]C(=O)OC(C)(C)C)([CH3:19])[CH3:18])[C:11]=2[C:10]2[N:9]=[CH:8][C:7]([Br:32])=[CH:6][C:5]=2[N:4]=1>C(O)C>[ClH:1].[ClH:1].[NH2:20][C:17]([CH3:18])([CH3:19])[CH2:16][N:15]1[C:11]2[C:10]3[N:9]=[CH:8][C:7]([Br:32])=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:28][O:29][CH2:30][CH3:31]
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)N
Temperature: 25 °C

Procedure:
Hydrogen chloride (56.74 g of a 2.2 M solution in ethanol, 124.8 mmol) was added to a suspension of tert-butyl {2-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-1,1-dimethylethyl}carbamate (15.40 g, 31.21 mmol) in anhydrous ethanol (120 mL), and the reaction mixture was heated at reflux for four hours and allowed to cool to room temperature. A precipitate had formed and was isolated by filtration, washed with a small volume of cold ethanol, and dried in a vacuum oven at 60° C. to provide 12.26 g of 1-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine dihydrochloride.