Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[CH3:19].CC(C)([O-])C.[Na+].ClCCl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:30]([N:20]([CH2:18][CH3:19])[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)=[CH:24][CH:23]=1)[CH3:31]
Reactant: CCCN1CCC(NCc2ccccc2)CC1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN1CCC(N(Cc2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)CC1
Yield: 61.7 %

Procedure:
A solution of N-benzyl-1-propyl-4-piperidinamine (3.47 g, 14.9 mmol), N, N-diethyl-4-bromobenzamide (3.82 g, 14.9 mmol), Pd2 dba3 (0.14 g, 0.149 mmol), (+)-BINAP (0.28 g, 0.448 mmol) and sodium t-butoxide (2.00 g, 20.9 mmol) in 18.5 mL of dry toluene was heated at 120° C. under Argon in a pressure vessel for 46 h. The mixture was cooled, and dichloromethane (75 mL) and water (75 mL) were added to the reaction flask. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (75 mL). The organic layers were combined and washed with brine (75 mL) and dried (Na2SO4). Evaporation of the solvent afforded a dark brown oil with some solid particles evident. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 3.75 g (62% yield) of N,N-diethyl-4-[benzyl(1-propylpiperidin-4-yl)amino]benzamide as a golden-brown oil. This material was dissolved in acetonitrile, and oxalic acid (0.82 g) was added. Upon addition of diethyl ether, a cream-colored precipitate came out of solution. Recrystallization from acetonitrile and diethyl ether afforded 2.41 g (32% yield) of a cream-colored solid, mp 92-99° C. MS (ES), m/z 408 (MH+). 300 MHz 1H NMR (DMSO-d6) δ0.89 (t, J=7.3 Hz, 3H), 1.08 (t, J=7.0 Hz, 6H), 1.56-1.73 (m, 2H), 1.82-2.10 (m, 4H), 2.94 (brt, J=7.8 Hz, 2H), 3.08 (br t, 2H), 3.31 (dd, J=6.9 Hz, 2H), 3.46 (br d, J=11.5 Hz, 2H), 4.18-4.35 (br m, 1H), 4.49 (br s, 2H), 6.74 (d, J=8.7 Hz, 2H), 7.20-7.35 (m, 7H). Elemental analysis: Calculated for C26H37N3O.C2H2O4.0.6H2O: C, 66.14; H, 7.97; N, 8.26. Found C, 65.90; H, 7.78; N, 8.01.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:37]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[CH:31]=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:38]>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:34]2[C:33]3[C:37]4[C:20]5([C:21]6[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=6)[NH:18][C:19]5=[O:38])[CH2:27][O:28][C:29]=4[CH:30]=[CH:31][C:32]=3[NH:36][O:35]2)[CH:5]=1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: BrCc1cccnc1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)N(Cc1cccnc1)ON3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 230-232° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 7.88-7.82 (m, 2H), 7.39-7.16 (m, 4H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 5.35-5.24 (m, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.84 (d, J=15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 162.9, 149.4, 148.8, 148.3, 144.8, 141.7, 135.1, 130.8, 129.8, 129.7, 123.9, 121.8, 119.4, 109.6, 106.9, 81.9, 57.2, 42.0; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:28].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCNC2)cc1)c1ccc(Cl)cn1
Temperature: 60 °C

Procedure:
To a stirred solution of (RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg) in THF (6 ml) was added dropwise a solution of hydrogen chloride in dioxane (2.9 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with diethyl ether, and were dried in vacuo at 60° C. to afford (RS)-5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide hydrochloride as a light yellow solid. MS (ISP): 304.2 ([{37Cl}M+H]+), 302.3 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:29]3[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ncccc3C#N)c2)CC1
Temperature: 60 °C
Yield: 58.1 %

Procedure:
To a solution of 4-(3-hydroxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.0 mmol) in DMSO (5.0 mL) were added Cs2CO3 (660 mg, 2.0 mmol) and 2-chloro-3-pyridinecarbonitrile (172 mg, 1.2 mmol). The mixture was heated at 60° C. for 90 min. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc (3×). The organic layer was separated and dried (Na2SO4). The crude residue was purified (FCC) to give 4-[3-(3-cyano-pyridin-2-yloxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (229 mg, 56%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C(=O)C>[N+:8]([C:7]1[C:2]([NH:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCc1cccs1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cccnc1NCc1cccs1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 180.0 parts of 2-chloro-3-nitropyridine, 122.0 parts of 2-thiophenemethanamine, 191.0 parts of sodium carbonate, 1 part of potassium iodide and 810 parts of N,N-dimethylacetamide was stirred for 1.50 hour at 100° C. The reaction mixture was poured into a lot of water (about 4000 parts). The whole was stirred overnight at room temperature. The precipitated product was filtered off and dried in vacuo at 40° C., yielding 251.5 parts of 3-nitro-N-(2-thienylmethyl)-2-pyridinamine; mp. 100° C. (interm. 1).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[C:10]([OH:21])=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CO>[OH:21][C@@H:10]1[C:9]2[CH:22]=[CH:23][C:6]([CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[CH:7][C:8]=2[O:13][CH2:12][C@H:11]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1ccc2c(c1)OCC(Cc1ccccc1)=C2O
Solvent: CO
Product: O=C(O)CCc1ccc2c(c1)OC[C@@H](Cc1ccccc1)[C@@H]2O
Yield: 30 %

Procedure:
Using the procedure of Example 2G with methanol as solvent at room temperature, the compound of step A (700 mg, 2.16 mmole) was reduced and the trans isomer 4-hydroxy-3-phenylmethyl-2H-1-benzopyran-7-propionic acid methyl ester saponified using the procedure of Example 2I to give the title compound (210 mg), 30% yield.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][N:8]([CH3:36])[C:9]([C:11]1[N:12]([CH3:35])[C:13]([C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:14]([CH3:16])[CH:15]=1)=[O:10]>C(OCC)(=O)C>[CH3:1][N:2]([CH:4]=[N:32][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:19]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:17]([C:13]3[N:12]([CH3:35])[C:11]([C:9]([N:8]([O:7][CH3:6])[CH3:36])=[O:10])=[CH:15][C:14]=3[CH3:16])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:34])[CH3:3]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
DMF (0.65 ml) and DMF acetal (0.19 g, 0.21 ml, 1.61 mmol) were added to a solution of N-methoxy-5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-N,1,4-trimethyl-1H-pyrrole-2-carboxamide (10d, 0.65 g, 1.46 mmol) in ethyl acetate (13 ml) under stirring at room temperature. The mixture was stirred at room temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 ml) and the mixture so obtained was washed with water (2×20 ml). The organic layer separated was dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by flash column chromatography using 4% methanol in DCM as an eluent to obtain the title compound 10e (0.62 g, 84.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30]Br>O1CCCC1.C(Cl)Cl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30][O:17][CH2:16][CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CCCOCc1cc(Br)ccc1F
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 49.9 %

Procedure:
3-[1-(t-Butoxycarbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahydrofuran (17 ml), cooled to −40° C., and treated with potassium t-butoxide (1 M in tetrahydrofuran, 3.62 ml, 3.62 mmol). The resulting mixture was stirred at −40° C. for about 35 minutes, then cooled to −78° C. To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg (50%) of the title intermediate as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(OC)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(C(=O)O)c1)CCCC2
Yield: 94.8 %

Procedure:
A solution of methyl 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (0.90 g, 4.09 mmol) in THF (50 mL), water (20 mL) and 1N NaOH (8.6 mL, 8.6 mmol) was stirred for 3 days at room temperature. The THF was evaporated and the mixture acidified to pH 1 with 1N HCl. The resulting precipitate was extracted with EtOAc, dried (MgSO4), filtered and concentrated to give the acid as a white solid (0.80 g, 95%). 1H NMR (DMSO) δ 12.79 (s, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 3.73 (s, 3H), 2.86 (s, 2H), 2.74 (s, 2H), 1.68 (m, 4H); MS m/z 205 (M−H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:11][NH:12][C:13]([C:15]1[N:16]([CH:31]([CH2:34][O:35][CH2:36][O:37][CH3:38])[CH2:32]O)[CH:17]=[C:18]([Br:30])[C:19](=[O:29])[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.C(N(CC)CC)C.CS(C)=O>[CH2:22]([O:21][C:20]1[C:19](=[O:29])[C:18]([Br:30])=[CH:17][N:16]2[C:31]([CH2:34][O:35][CH2:36][O:37][CH3:38])=[CH:32][N:12]([CH2:11][C:10]3[CH:39]=[CH:40][C:41]([F:42])=[C:8]([Cl:7])[CH:9]=3)[C:13](=[O:14])[C:15]=12)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCOCC(CO)n1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1ccc(F)c(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCOCc1cn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OCc3ccccc3)c(=O)c(Br)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.2 %

Procedure:
To a solution of oxalyl chloride (0.245 ml) in methylene chloride (1 ml) was added dropwise a solution of dimethyl sulfoxide (0.269 ml) in methylene chloride (1 ml) under a nitrogen stream at −78° C. and the mixture was stirred for 10 min. A solution of 3-benzyloxy-5-bromo-1-(1-hydroxy-3-methoxymethoxy-2-propyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide (410 mg) in methylene chloride (16 ml) was added at the same temperature over 5 min. After stirring for further 10 min after the completion of the dropwise addition, triethylamine (1.37 ml) was added and the mixture was heated to room temperature. The mixture was stirred at room temperature for 1 hr and concentrated. Water was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in chloroform (8 ml), and N,N-diisopropylethylamine (0.734 ml) and methanesulfonyl chloride (0.101 ml) were successively added under ice-cooling. After stirring at room temperature for 2 hr, methanesulfonyl chloride (0.05 ml) was added and the mixture was further stirred for 1 hr. The reaction mixture was concentrated, and aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with saturated brine, dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:2-ethyl acetate) to give 9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione (163 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=O)(=[O:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][N:34](C)[CH2:35]CCN=C=NCC.CNC.CO>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:17]([O:16][C:14](=[O:15])[NH:13][C@H:9]([C:10](=[O:12])[N:34]([CH3:35])[CH3:33])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
(2S)-6-Acetylamino-2-(tert-butoxycarbonylamino)hexanoic acid (Purchased at Bachem, 5.0 g, 17.3 mmol) was dissolved in dichloromethane (100 ml) and N,N-dimethylformamide (50 ml). 1-Hydroxybenzotriazole hydrate (2.65 g, 17.3 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.32 g, 17.3 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A 33% solution or dimethylamine in methanol (16.4 ml, 121 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (250 ml) and washed with a 10% aqueous solution of sodium hydrogensulfate (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed. The crude product was purified by flash chromatography on silica (120 g), using dichloromethane/methanol (10:1) as eluent to give 3.00 g of ((1S)-5-acetylamino-1-(dimethylcarbamoyl)pentyl)carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][CH:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C1(C2C=CC=CC=2C(NC2C=CC(C(Cl)=O)=CC=2)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[CH:24][C:16]=2[Cl:15])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: OCCC1=CC=Nc2ccccc2S1
Agent: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2C=CC(CCO)Sc3ccccc32)c(Cl)c1

Procedure:
A mixture of 2-(2-hydroxyethyl)-1,5-benzothiazepine as prepared in Example 2 (0.070 g, 0.34 mM) and N,O-bis(tri-methylsilyl)acetamide (0.15 ml, 0.67 mM)was treated as described in Example 3 with 2-Chloro-4-(2-methyl-5-fluorobenzoylamino)benzoyl chloride (0.11 g, 0.32 mM) substituted for 4-(2-phenylbenzoylamino)benzoyl chloride to give the product as a white solid. m/z (MH+) 500.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[C:15](OCC)=[O:16].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][OH:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cn1cc2c([C@@H]3C[C@H]3CO)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of trans-ethyl 2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropanecarboxylate (2.00 g, 7.63 mmol) in tetrahydrofuran (76 mL) was slowly added a solution (1 M, 22.9 ml, 22.9 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.51 g, yield 90%
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([CH:12]([OH:13])[C@@H:10]([C@H:8]([C@@H:6]([CH2:5][OH:4])[OH:7])[OH:9])[OH:11])[CH:16]=[CH2:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: C=CCBr
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A 5 L three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condenser, was charged with 1.8 liters of ethanol, 0.3 liters of water, 300 g (2.00 mole) of D-xylose, 242 g (2.04 mole) of tin powder (−325 mesh), and 242 g (2.00 mole) of allyl bromide. The mixture was stirred and slowly heated to reflux—a significant exotherm and gas evolution was observed at 60° C. The gray suspension was stirred at reflux for three days, in which time the reaction mixture turned an orange/brown color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 400 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 320 g. 1H NMR (300 MHz, D2O, ppm): 2.33–2.39 (m, 2H), 3.55–3.89 (m, 6H), 5.14–5.23 (m, 2H), 5.89 (m, 1H). The syrup was used without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>ClCCl.CN(C1C=CN=CC=1)C>[O:7]=[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: NCCc1ccccn1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.5 %

Procedure:
To a solution of 5.0 g (50 mmol) of succinic anhydride in 50 mL of dichloromethane was added 550 mg of DMAP and 6.1 g (50 mmol) of 2-(2'-aminoethyl)pyridine. An exothermic reaction resulted. The reaction was refluxed for 1 h and cooled to room temperature and stirred for 48 h. The reaction is worked up by concentrated in vacuo; the resulting solid was dissolved in pH 4 buffer and extracted three times with 4:1 ethyl acetate/tetrahydrofuran after the aqueous solution had been saturated with ammonium sulfate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was recrystallized from ethyl acetate/methanol to give 5.5 g (50%) of 4-oxo-4-[[2-(2-pyridinyl)ethyl]amino]butanoic acid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.