Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)c1
Yield: 79.4 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,4-dimethoxyphenylboronic acid (171 mg, 0.94 mmol) were reacted. After purification the title compound (136 mg, 80% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=4.8 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.68 (ad, J=7.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.59 (ad, J=8.3 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 3H), 2.96 (m, 1H), 0.70(m, 4H). MS APCI, m/z=365.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[C:7](Cl)(Cl)=[O:8].C1(C)C=CC=CC=1.[F:18][C:19]([F:55])([F:54])[C:20]1[CH:21]=[C:22]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:23][N:24]([C:41]1[N:42]=[N:43][N:44]([CH3:46])[N:45]=1)[C@H:25]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]2[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:26]1=2.N1C=CC=CC=1>ClCCl>[CH2:2]([CH:3]([O:6][C:7]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:25]([N:24]([CH2:23][C:22]2[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=[C:20]([C:19]([F:18])([F:55])[F:54])[CH:21]=2)[C:41]2[N:42]=[N:43][N:44]([CH3:46])[N:45]=2)[C:26]2[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([F:39])([F:38])[F:40])=[CH:32][C:27]1=2)=[O:8])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(CC)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a mixture of pentan-3-ol (0.117 ml, 1.08 mmol) di-isopropyl ethyl amine (0.189 ml, 1.08 mmol) in dichloromethane at 0° C. with 20% phosgene in toluene (0.480 ml, 0.905 mmol). Stir the mixture at 0° C. for 10 minutes, and then warm up to room temperature for an hour. Add a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (0.100 mg, 0.181 mmol) (Example 3, Step 18)) in dichloromethane (1.00 ml) followed by pyridine (0.0730 ml, 0.905 mmol). Continue the reaction at room temperature overnight. Dilute the mixture with dichloromethane (5.05 ml), wash with 1N hydrochloric acid (5.00 ml) and water (3×5.00 ml), dry over Na2SO4 and concentrated. Purify by silica gel chromatography (gradient eluent, 0-25% ethyl acetate in hexane) to provide the titled compound (0.0710 g, 59%). MS (ES+): 667 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3ccc(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 14 h
Yield: 0.1 %

Procedure:
To a solution of 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene)-azetidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.16 mmol) in MeOH (10 mL) was added Pd/C (10%, 0.02 g) and the mixture was stirred under H2 (50 psi) for 14 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (0.075 mg, 69%) as a pale yellow powder. LC/MS (Table 1, Method 2) Rt=1.217 min; MS m/z: 409 [M+23]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[N:21][OH:22])[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[C:38](C1NC=CN=1)(C1NC=CN=1)=[O:39].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][C:38](=[O:39])[O:22][N:21]=4)[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C(N)=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 79.7 %

Procedure:
A mixture of Example 8C (2.62 g, 5.0 mmol), carbonyl diimidazole (0.973 g, 6.00 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.829 mL, 5.50 mmol) in dioxane (20 mL) was refluxed for one hour, cooled and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate/hexane (1:3) to give the title compound as a solid (2.19 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[NH:6]2.[C:17](Cl)([Cl:19])=[O:18]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:6]1[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[C:11]2=[C:2]([CH3:1])[S:3][CH:4]=[C:5]12)=[O:18]
Reactant: Cc1scc2c1C(=O)Nc1ccccc1N2
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1scc2c1C(=O)Nc1ccccc1N2C(=O)Cl

Procedure:
From 4,9-dihydro-1-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-1-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained, m.p. 235°-236° C. (chloroform);
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:4]([NH:6][C@@H:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])=[O:9])=[O:5].CO[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:4]([NH:6][C@H:7]([C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])=[O:9])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, a 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (1.0 g, 2.0 mmol, from Reference Example 104) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.17 g, 4.0 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (240 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a hard white foam (50 mg). MS (ES+): (M+H)=475.0
Reaction SMILES: C([O:3][C:4](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:5][F:6])C.Cl>C(OCC)C>[F:6][CH2:5][C:4](=[O:3])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: CCOC(=Cc1cccc(OC)c1)CF
Agent: Cl
Solvent: CCOCC
Product: COc1cccc(CC(=O)CF)c1
Yield: 98.8 %

Procedure:
2-Ethoxy-1-fluoro-3-(3-methoxyphenyl)prop-2-ene (8.40 g, 0.040 mol) is stirred with a saturated solution of hydrogen chloride in diethyl ether (80 ml) overnight. The ether layer is separated, washed with water, dried (MgSO4) and filtered. Concentration of the solvent affords 1-fluoro-3-(3-methoxyphenyl)-2-propanone (7.200 g); NMR (CDCl3): 3.73 ppm (m, 5H); 4.77 ppm (d, JHF =48 Hz, 2H); 6.57-7.33 ppm (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[OH:14][CH2:15][CH2:16][NH2:17]>>[OH:14][CH2:15][CH2:16][N:17]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:13]
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Reactant: NCCO
Product: Cc1cc2c(n(CCO)c1=O)CCCC2=O

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and 2-hydroxy- ethylamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:34])[NH:31]2)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:34])[NH:31]2)=[CH:27][CH:26]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OCCCN1CCOCC1
Yield: 0.1 %

Procedure:
Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.47 mol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline (157 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH2:8][C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>N1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:25]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[CH2:6][CH2:5]2
Reactant: c1ccncc1
Reactant: O=C1CCc2cc(Cl)c(Cl)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNC1
Product: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2

Procedure:
9.00 g (0.042 mol) of 6,7-dichloro-3,4-dihydro-2(1H)-naphthalenone and 0.3 g of p-toluenesulfonic acid are dissolved in 200 ml of pyridine 3.5 ml (0.042 mol) of pyrrolidine are added dropwise thereto and the mixture is boiled under reflux for 2 hours. Distillation of the solvent in a vacuum, addition of 200 ml of ether and filtering off the crystals formed yields 1-(6,7-dichloro -3,4-dihydro-2-naphthyl)pyrrolidine with melting point 1-142°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1)OCc1ccccc1
Yield: 74.8 %

Procedure:
Treatment of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.6 g, 5.4 mmol) with diisopropylethylamine (1.197 g, 9.26 mmol) and benzyl chloroformate (1.02 g, 5.96 mmol) generally according to the procedure described for Intermediate 12 afforded 1.59 g (75%) of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.56 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 69.11; H, 5.07; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=15.935 min Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt=18.546 min, Chiralcel OD, hexane:isopropanol 9:1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]2[S:25][C:26]([CH2:28][NH:29][CH3:30])=[CH:27][C:15]=2[N:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Cl:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]2[S:25][C:26]([CH2:28][N:29]([CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH3:30])=[CH:27][C:15]=2[N:14]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To a solution of 1-methanesulfonyl-piperidine-4-one (173 mg; prepared from N-BOC-piperidone by reaction of piperidone-4-one TFA salt with methane sulfonyl chloride) stirring in anhydrous 1,2-dichloroethane (10 ml), was added 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-ylmethyl methylamine (291 mg; as prepared from 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-carbaldehyde and methylamine under reductive amination conditions), followed by glacial acetic acid (59 μl). Sodium triacetoxyborohydride (269 mg) was added in several aliquots and then stirred for 12 hours at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with 50% sodium hydrogen carbonate solution, brine, and dried (MgSO4). The solvents were removed in vacuo to give a residue which after purification by flash silica chromatography gave (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-(1-methanesulphonyl-piperidin-4-yl)-methyl-amine (408 mg), which was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole, to give, after flash silica purification the title compound (55 mg) as a white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH:13]([CH3:15])[CH3:14].[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[N+:24]=[N-:25].O>CN(C=O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:25]=[N:24]1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C(C)C
Reaction time: 0.25 h

Procedure:
DBU (3.6 ml; 24.07 mmol; 1.10 eq.) was dissolved in DMF (45 ml) and put under nitrogen atmosphere. Ethyl isobutyrylacetate (Aldrich, 3.807 g; 24.07 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (3 g; 21.858 mmol; 1 eq.) in DMF (10 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 5 hours. Water (80 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (2×100 mL). Combined organics were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 278.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:17](OCC)(=[O:20])[NH:18][NH2:19]>C(O)CCC>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:17](=[O:20])[NH:18][N:19]=3)[N:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: CCOC(=O)NN
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Solvent: CCCCO
Product: COc1ccc(-c2ccc3n[nH]c(=O)n3n2)cc1F

Procedure:
A mixture comprising 4.0 g. of 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine (U.S. Pat. No. 4,092,311), 3.54 g. of ethyl carbazate and 100 ml. of butanol is stirred at reflux for 3 days and then cooled in an ice bath. The resulting solid is collected by filtration and dried, giving 2.4 g. of the desired product as a tan solid, m.p. 289°-290° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[I:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[I:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(I)c1
Product: O=C(O)Cc1ccccc1Nc1cccc(I)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-iodoaniline to yield 2-[(3-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[N+](C1C=CC([O:39][C:40]([N:42]2[C@@H:46]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[CH:48]=3)[C@H:45]([CH2:55][O:56][CH:57]3[CH2:62][CH2:61][CH2:60][CH2:59][O:58]3)[O:44][C:43]2=[O:63])=O)=CC=1)([O-])=O.C(OCC)(=O)C>CCCCCC>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:10]1[CH2:11][CH2:12][CH:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:40]([N:42]3[C@@H:46]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[CH:48]=4)[C@H:45]([CH2:55][O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[O:44][C:43]3=[O:63])=[O:39])[CH2:3]2)[CH2:8][CH2:9]1)#[N:16]
Reactant: N#Cc1ccccc1N1CCC(N2CC[C@@H](N)C2)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)O[C@@H](COC2CCCCO2)[C@@H]1c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: N#Cc1ccccc1N1CCC(N2CC[C@@H](NC(=O)N3C(=O)O[C@@H](COC4CCCCO4)[C@@H]3c3ccc(F)c(F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of 2-[4-(3-amino-(3R)-pyrrolidin-1-yl)piperidin-1-yl]benzonitrile (166 mg, 0.44 mmol) in dry, degassed N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (230 μL, 1.3 mmol) followed by (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (210 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 4 h when the volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium carbonate solution (8×100 mL), brine (1×100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide as a white foam (156 mg, 0.26 mmol, 59%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH:22]([C@:25]1([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[N:41][CH:42]=C(C(F)(F)F)[CH:44]=3)[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]1)([CH3:24])[CH3:23].[CH3:49][CH:50]1[C:55](=O)[CH2:54][CH2:53][O:52][CH2:51]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:22]([C@:25]1([C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:39]3[CH:40]=[N:41][CH:42]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:44]=3)[CH2:37][CH2:38]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH:30][CH:55]2[CH2:54][CH2:53][O:52][CH2:51][CH:50]2[CH3:49])[CH2:26]1)([CH3:24])[CH3:23]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)cyclopentanamine tris(trifluoroacetate) (25 mg, 0.034 mmol), 3-methyltetrahydro-4H-pyran-4-one (11 mg, 0.10 mmol) and triethylamine (0.024 mL, 0.17 mmol) in methylene chloride (2 mL) was added sodium triacetoxyborohydride (22 mg, 0.10 mmol). The mixture was stirred under N2 at room temperature overnight and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9:1:0.5) to give 14 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral to give peak 1 and peak 2. MS calculated for C25H37F3N4O2: (M+H) 483; found 483.2.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[CH:8][N:7]=1)[CH3:5])=[O:2].[OH-].[Na+].Cl.[O-]C#[N:19].[Na+]>C(Cl)(Cl)Cl.CO>[NH:3]([C@@H:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[CH:8][N:7]=1)[CH3:5])[C:1]([NH2:19])=[O:2]
Reactant: N#C[O-]
Reactant: C[C@@H](NC=O)c1ncc2sccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@@H](NC(N)=O)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To 0.234 g of 5-[(R)-1-(formylamino)ethyl]imidazo[5,1-b]thiazole (Preparation 18) was added 3 ml of an aqueous solution of 2N sodium hydroxide, and the mixture was stirred at room temperature for 16 hours. After the reaction mixture was adjusted to pH 5 with 5N hydrochloric acid and heated to a temperature of 70° C., 0.160 g of sodium cyanate was added and the resulting mixture was stirred at 70° C. for 1 hour and at room temperature for further 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with 50 ml of methylene chloride and 50 ml of methanol to stir well the mixture before removal of insolubles by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified on Sephadex LH20 (eluent: chloroform-methanol=1:1) to give 0.221 g of the title compound (yield 87%). NMR (DMSOd-6) δ: 1.45 (3H, d, J=6.9 Hz), 5.13 (1H, dq, J8.7 Hz, 6.9 Hz), 5.52 (2H, br), 6.45 (1H, d, J=8.7 Hz), 6.92 (1H, s), 7.20 (1H, d, J=4.2 Hz), 7.80 (1H, d; J=4.2 Hz).