Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)C4CC4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.65 g, 2.10 mmol) in acetonitrile (50 mL). After stirring for 30 min, cyclopropanecarbonyl chloride (0.24 g, 2.31 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (100 mL) to afford N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}cyclopropylcarboxamide (0.36 g, 50%) as a white solid: mp 262–264° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 8.63 (t, J=5.7 Hz, 1H), 7.65–7.47 (m, 3H), 5.18–5.11 (dd, J=5.0 and 13.2 Hz, 1H), 4.46 (d=17.3 Hz, 1H), 4.38–4.31 (m, 3H), 3.00–2.85 (m, 1H), 2.65–2.30 (m, 2H), 2.04–1.99 (m, 1H), 1.64–1.54 (m, 1H), 0.69–0.65 (m, 4H); 13C NMR (DMSO-d6) δ 172.82, 172.69, 170.96, 168.03, 140.08, 134.76, 131.66, 130.70, 128.30, 121.64, 51.54, 46.15, 31.16, 22.59, 13.47, 6.27; Anal. Calcd. For C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.55; N, 12.33.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1
Yield: 36.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (150 mg. 0.42 mmol), acetic acid (24 μL, 0.42 mmol), 4-aminomethyl-benzoic acid methyl ester (170 mg, 0.84 mmol) and sodium triacetoxyborohydride (268 mg, 1.27 mmol) to afford 74 mg (36%) of the desired product after purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:15][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH:32]([CH3:34])[CH3:33]>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:32]([CH3:34])[CH3:33])[CH:25]=1)[CH2:15][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O)c1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(OC(C)C)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
Sodium hydride (48 mg, 1.2 mmol) was added to a solution of 30 (300 mg, 0.8 mmol) in THF (10 ml) and the reaction mixture was stirred at rt for 20 min. 2-Iodopropane (0.12 ml, 1.2 mmol) was added and the reaction mixture was stirred at rt for 26 h. Further 2-iodopropane (0.36 ml, 3.6 mmol) was added and the reaction mixture was heated at 60° C. 24 h. The solution was concentrated in vacuo, water was added and the aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 50 g, 100% hex-100% EtOAc over 35 min) afforded the title compound (259 mg, 77%) as a colourless oil; 1H NMR (270 MHz; CDCl3) 1.31 (6H, d, J=6.2 Hz, 2×CH3), 2.66-2.75 (4H, m, 2×CH2), 3.54 (2H, s, CH2), 3.62 (2H, s, CH2), 3.80 (3H, s, OCH3), 4.54 (1H, septet, J=6.2 Hz, CH), 5.09 (2H, s, CH2Ph), 6.50 (1H, s, CH), 6.61 (1H, s, CH), 6.77-6.81 (1H, m, CH), 6.91-6.94 (2H, m, 2×CH), 7.16-7.47 (6H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 22.18 (CH3), 28.77 (CH2), 50.80 (CH2), 55.85 (CH2), 56.16 (OCH3), 62.85 (CH2), 69.75 (CH), 71.18 (CH2), 110.13 (CH), 114.30 (CH), 114.59 (CH), 116.47 (CH), 126.31 (C), 127.35 (CH), 127.55 (C), 127.82 (CH), 128.58 (CH), 129.32 (CH), 137.40 (C), 140.16 (C), 146.69 (C), 147.91 (C), 158.02 (C). LC/MS (APCI−) tr=7.47 min, m/z 416.35 (M−H)−.
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][CH2:5][O:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([NH:24][C:25]2[C:30]([CH:31]=O)=[CH:29][N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1.C(OCC)(=O)C.O>[CH:19]1([N:24]2[C:25]3[N:26]=[C:27]([S:33][CH3:34])[N:28]=[CH:29][C:30]=3[CH:31]=[C:4]([CH2:5][O:6][CH3:7])[C:3]2=[O:8])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COCCC(=O)OC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Yield: 24.1 %

Procedure:
3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR δ (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15]>>[CH3:1][C@H:2]1[CH2:7][CH2:8][N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)C[C@H](C)C(=O)OC
Reactant: C[C@H](N)CO
Product: C[C@H]1CCN([C@@H](C)CO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (S)-dimethyl 2-methylsuccinate and (S)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.57 (dd, 1H), 3.32 (dd, 1H), 3.02 (br s, 1H), 2.81 (dd, 1H), 2.69 (m, 2H), 2.60 (m, 1H), 2.21 (m, 1H), 2.12 (dd, 1H), 1.98 (m, 1H), 1.32 (m, 1H), 1.04 (m, 6H); MS: 144.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].[OH2:23].Cl>O1CCOCC1>[C:17]([O:16][CH2:14][C:13]([C:11]1[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=1)([OH:20])[CH3:19])(=[O:23])[CH3:18]
Reactant: C=CCOC(=O)Nc1nc(C(C)(O)C(=O)OCC)cs1
Reactant: O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)Nc1nc(C(C)(O)COC(C)=O)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropionate (2.75 g) in 1,4-dioxane (25 mL) was added sodium borohydride (0.962 g) under ice-cooling. Further, water (0.5 mL) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Concentrated hydrochloric acid (8 mL) was added thereto at an internal temperature of 20° C. or lower under ice-cooling, followed by concentration. A white solid was separated by filtration while washing the obtained residue with methanol. The obtained white solid was dissolved in pyridine (15 mL), and acetic anhydride (2.59 mL) was added thereto at room temperature, followed by stirring for 2.5 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. After concentration, 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (2.71 g) was obtained as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C@H:34]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([NH:67][C@H:68]([C:71]([NH:73][C@H:74]([C:90]([NH:92][C@H:93]([C:99]([OH:101])=[O:100])[CH2:94][CH2:95][C:96](=[O:98])[OH:97])=[O:91])[CH2:75][CH2:76][CH2:77][CH2:78][NH:79]S(C1C=CC(C)=CC=1)(=O)=O)=[O:72])[CH2:69][OH:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:64])[NH2:63])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:35][CH2:36][C:37](=[O:39])[OH:38])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4]>N>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C@H:34]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([NH:67][C@H:68]([C:71]([NH:73][C@H:74]([C:90]([NH:92][C@H:93]([C:99]([OH:101])=[O:100])[CH2:94][CH2:95][C:96](=[O:97])[OH:98])=[O:91])[CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])=[O:72])[CH2:69][OH:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:63])[NH2:64])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:35][CH2:36][C:37](=[O:38])[OH:39])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: N
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
51.0 Milligrams of H-Thr-Asn-Leu-Gln-Glu-Ser-Leu-Arg-Ser-Lys(Tos)-Glu-OH was dissolved in liquid ammonia being dried with metallic sodium previously, then small pieces of metallic sodium were added to the solution under stirring condition until the color of the reaction mixture is changed to blue and kept it for 30 seconds to 1 minute. Further crystals of NH4Cl were added to the reaction mixture, an excess metallic sodium was neutralized, after ammonia was completely removed by distillation at a room temperature, the readtion product was subjected to gel-filtration with Sephadex G-25 gel by using 50%-acetic acid as the eluting solvent, for collecting the desired fraction, and the lyophilizing the raction by adding water after concentration, to obtain 32 mg of the desired product (peptide of the present invention). Hereinafter, this product is referred to as [Peptide F].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OC(C)(C)C)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.0 g) in N,N-dimethylformamide (100 ml) was added tert-butyl bromoacetate (2.9 g), and the solution was stirred for 3 hours at ambient temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo to give tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 3.2 g), mp 188°-190° C. (dec.).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[NH:28][CH:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[NH:28][CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2cc[nH]c12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), 4-chloro-5H-pyrrolo[3,2-d]pyrimidine from Example 20 (155 mg, 0.99 mmol, 0.99 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.03 mmol, 3.02 equiv, 98%). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The residue was purified by applying onto a C18 column eluted with water/acetonitrile (95:5-20:80) to afford 150 mg (41%) of 147 as a light-yellow solid. LC-MS (ES, m/z): 355 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.49 (s, 1H), 7.85-7.48 (m, 9H), 7.32-7.30 (m, 1H), 6.63 (d, 1H), 5.81-5.74 (m, 1H), 1.89 (d, 3H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[F:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cccc2c1CNCCS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCSc2cccc(F)c2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of methanesulphonyl chloride (1.83 g) in dichloromethane (30 ml) was added dropwise at room temperature to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.65 g, prepared in a similar manner to its hydrochloride, Example 3 above) and triethylamine (1.6 g) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature for 20 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 3.3 g (m.p. 115°-117° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1>C(O)C.[Pd]>[NH2:8][C:5]1[C:4]([OH:11])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ncc(F)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ncc(F)cc1O

Procedure:
5.6 g of 5-fluoro-2-nitropyridin-3-ol (Example 7A; 36 mmol) were dissolved in 2 l of ethanol, a catalytic amount of palladium on activated carbon (10%) was added and the mixture was hydrogenated under standard hydrogen pressure for 16 h. The mixture was filtered off through silica gel and the filtrate was concentrated (product batch 1). The filter cake was rinsed with methanol until the colour of the filtrate was no longer yellowish. The filtrate was concentrated, giving a second product batch. This gave 4.26 g (85% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:4]1[CH:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:22])=[O:19]
Reactant: Cc1cc(N)cnc1-c1ccccc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CC#N
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cnc1-c1ccccc1
Reaction time: 4.5 h

Procedure:
5-Methyl-6-phenyl-3-pyridylamine (0.4 gram) in 20 ml of acetonitrile was added to 2,6-dichlorobenzoyl isocyanate (0.5 gram) under nitrogen and at room temperature. After about 10-20 minutes a precipitate formed. The reaction mixture was then stirred for about 4-5 hours and the product was filtered and washed with acetonitrile, yield, 580 mg, m.p. 202°-205° C. A small portion of the product was recrystallized from ethanol, m.p. 204°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.Cl.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: NCC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(NCC2CCOCC2)n1
Temperature: 110 °C
Yield: 81.4 %

Procedure:
A mixture of 2-bromo-6-fluoropyridine (750 mg, 4.26 mmol) in DMSO (3 mL) was mixed with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (775 mg, 5.11 mmol) and NEt3 (1.426 mL, 10.23 mmol). The resulting mixture was heated at about 110° C. for 18 hr. The mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a resulting residue. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (B1, 940 mg) as a white solid. LCMS (m/z): 271.0/272.9 [M+H]+; Retention time=0.81 min.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([OH:33])[CH2:31][CH3:32])=[CH:10][CH:9]=1.[C:34](OC=C)(=O)[CH3:35]>C1C(Cl)=CC=C(Cl)C=1>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([O:33][CH:34]=[CH2:35])[CH2:31][CH3:32])=[CH:10][CH:9]=1
Reactant: C=COC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To a suspension of sodium carbonate (16.4 mg, 0.155 mmol) in dichlorobenzene (0.5 mL) were added di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (8.7 mg, 0.0129 mmol), 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100.0 mg, 0.155 mmol) and vinyl acetate (47.7 μL, 0.517 mmol). The reaction mixture was stirred at 100° C. for 3.5 hrs. The mixture was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (66.4 mg, 0.161 mmol, 62%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:19][C:20]#[N:21])[CH2:18][NH:17][CH2:16]3)[CH:14]=2)[O:4]1.Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([CH2:19][C:15]1([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:22])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][N:17]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)[CH2:18]1)#[N:21]
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A mixture of {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (400. mg, 1.23 mmol), methyl 5-chloropyrazine-2-carboxylate (223 mg, 1.29 mmol), cesium carbonate (800 mg, 2.5 mmol), palladium acetate (28 mg, 0.12 mmol) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (150 mg, 0.25 mmol) in toluene (5 mL) was stirred at 100° C. for 3 h. After the reaction mixture was cooled to room temperature, the solid was separated, and washed with ethyl acetate twice. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.28 g). LCMS (M+H)+: m/z=425.2.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[NH:35][NH2:36]>[Cu]I.O1CCOCC1>[C:39]([O:38][C:34]([N:35]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[NH2:36])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Ic1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(N)c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 87.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (50 mg, 0.263 mmol, 5.1 mol %), 1,10-phenanthroline (100 mg, 0.555 mmol, 11 mol %), 4-iodobiphenyl (1.45 g, 5.18 mmol), Cs2CO3 (2.30 g, 7.06 mmol), evacuated and backfilled with argon. tert-Butyl carbazate (825 mg, 6.24 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 1×1 cm pad of silica gel eluting with 50 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 4:1; 20 mL fractions). Fractions 9-20 provided 1.29 g (88% yield) of the product as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.64-7.59 (m, 2H), 7.57 (s, 4H), 7.48-7.43 (m, 2H), 7.38-7.33 (m, 1H), 4.50 (s, 2H), 1.56 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]>CO.[Pd]>[OH:3][CH:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2[nH]c(=O)oc2c1
Agent: [Pd]
Solvent: CO
Product: CC(O)c1ccc2[nH]c(=O)oc2c1

Procedure:
2.5 g (14.1 mmol) of 6-acetyl-3H-benzoxazol-2-one are dissolved in 150 ml of methanol, and the mixture is stirred for 5 h with 2.5 g of palladium on activated carbon (5%) and under a hydrogen atmosphere. The catalyst is filtered off with suction and rinsed with methanol. The filtrate is evaporated to dryness and dried in vacuo.