Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: O=C1c2ccccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Yield: 88.1 %

Procedure:
A solution of 1.0 g (0.0028 mol) of (S)-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 50 ml of tetrahydrofuran was treated with 4.6 ml (0.034 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate/tetrahydrofuran 2:1 as the eluent. There were obtained 1.04 g (95%) of (S)-1-(4-dipropylaminomethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as a pale yellow oil; [α]D20 =-253.8° (MeOH, c=1%).
Reaction SMILES: C(O[C@@:5]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)=[C:23]2[Cl:43])([C:12]1[C:13]([CH3:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:6]1[N:10]([CH3:11])[N:9]=[N:8][CH:7]=1)(=O)C.[NH3:44].CO>>[Cl:43][C:23]1[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:5]([C:12]3[C:13]([CH3:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)([C:6]3[N:10]([CH3:11])[N:9]=[N:8][CH:7]=3)[NH2:44])[CH:21]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=1
Reactant: COc1nc2ccc([C@](OC(C)=O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: COc1nc2ccc(C(N)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 65 °C

Procedure:
A mixture of (S)-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methyl acetate (646 mg, 1.06 mmol, Intermediate 55) and ammonia in MeOH (3.3 mL, 23 mmol, 7.0 M) in a sealed pressure tube was heated at 65° C. for 18 h, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g silica gel column, 50-100% EtOAc in heptanes, and 5-10% MeOH in CH2Cl2) to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=2.02 Hz, 1H), 7.82 (d, J=9.09 Hz, 1H), 7.51 (d, J=8.08 Hz, 2H), 7.37-7.44 (m, 3H), 7.08 (d, J=8.08 Hz, 1H), 7.02 (s, 1H), 6.98 (d, J=8.08 Hz, 1H), 4.34 (s, 2H), 4.09 (s, 3H), 3.94 (s, 3H), 2.56 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(C(C(C([O-])=O)O)O)([O-])=O.[Na].[K]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cc(I)ccc1C(=O)OC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1cc(I)ccc1CO
Reaction time: 2 h

Procedure:
A 1M solution of DiBAIH (87.5 ml, 87.5 mmol) is added dropwise to a solution of methyl 2-heptyloxy-4-iodobenzoate obtained in Step a (14 g, 43.7 mmol) in toluene (450 ml), at 0° C. After stirring for 2 hours, a saturated solution of mixed tartrate of sodium and of potassium is added and then the desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9:1 mixture. After evaporation of the solvents, 13.64 g (90%) of the expected compound are recovered in the form of a yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:23])[C:12]([CH3:22])=[C:13]([C:19](=[O:21])[CH:20]=2)[C:14]([O:16]CC)=[O:15])=[CH:6][CH:5]=1>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH3:23])[C:12]([CH3:22])=[C:13]([C:19](=[O:21])[CH:20]=2)[C:14]([OH:16])=[O:15])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)n(C)c(-c2ccc(Cl)cc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)c(=O)cc(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
1.5 g (0.019 mol) of 50% aqueous sodium hydroxide is added to a suspension of 2.9 g (0.0095 mol) ethyl 6-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinate in 75 ml of water. The mixture is refluxed and stirred for 15 min. and cooled to room temperature. The solution is extracted with methylene dichloride and the aqueous solution is acidified to pH 1 with 12N hydrochloric acid. The suspension formed is vacuum filtered and the filter cake is dried to afford 1.8 g (68% yield) of 6-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinic acid, mp 236°-238° C. dec.
Reaction SMILES: [I:1][C@@H:2]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12][C@H:3]1[O:4][Si](CC)(CC)CC.C1COCC1.FC(F)(F)C(O)=O>O>[I:1][C@H:2]([C@H:15]([C@@H:14]([C@@H:13]([CH2:18][OH:19])[OH:12])[OH:17])[OH:16])[CH:3]=[O:4]
Reactant: CC[Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1I
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C[C@H](I)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Mixture of 2-deoxy-2-iodo-1-O-triethylsilyl-β-D-glucopyranose (VI) (0.1 g), THF (2 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL) was prepared and stirred at room temperature. Progress of the reaction was monitored by TLC and after substrate disappearance reaction mixture was washed with dichloromethane (5×10 mL). The remaining water solution was lyophilized and such obtained crude solid residue was purified by column chromatography (SilicaGel 60, Merck) using chloroform, chloroform:methanol 9:1, 7:3 as eluents, to give (0.05 g) of 2-deoxy-2-iodo-D-glucose (VII). Yield 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc(Oc2ccc(Cl)cc2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (2.36 g, white solid) from 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone (2.02 g, 7.72 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14].C(O)C>C(O)(=O)C>[NH:13]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Clc1ccc2ccccc2n1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NNc1ccc2ccccc2n1

Procedure:
2-Hydrazinoquinoline (35.70 g; 0.224 mol) obtained in a customary manner (e.g., as disclosed in J. Chem. Soc., 103, 1978) from 2-chloroquinoline and hydrazine hydrate, 56.29 g (0.149 mol, mol ratio 1.5) of di-p-diethylaminostyryl ketone, 450 ml of ethanol and 74.8 ml of acetic acid were refluxed for 3 hours with stirring. The reaction mixture was cooled with water. The crystals that precipitated were separated by filtration, and hot-filtered using 150 cc of ethanol to afford 27.12 g (yield 35%) of yellow crystals having a melting point of 180° to 182° C. Recrystallization from methyl ethyl ketone afforded crystals having a melting point of 182° to 183° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>CN(C)C=O>[O:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:22][CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (7.5 mg, 0.19 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 1-Chloromethyl-4-phenoxy-benzene (32.8 mg, 0.15 mmol) described in Manufacturing Example 34-1-1 was then added to the mixture and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (41 mg, 86%, purity: 90%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:67](O)(=[O:71])[C@@H:68]([CH3:70])[OH:69]>C1COCC1>[OH:69][C@H:68]([CH3:70])[C:67]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:71]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@@H](C)O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added diisopropylethylamine (0.22 mL, 1.26 mmol), HATU (175 mg, 0.46 mmol) and D-(−)-lactic acid (41 mg, 0.46 mmol). The reaction mixture was stirred at RT for 18 hours and then concentrated in vacuo. The resultant residue was partitioned between DCM and an aqueous saturated sodium bicarbonate solution and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give a cream solid that was freeze-dried from methanol and water to give 318 as a white solid (59 mg, 32%). LCMS: RT=4.44 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1H, d, J=8.19 Hz), 8.05 (1H, s), 7.18 (1H, ddd, J=8.24, 4.14, 1.84 Hz), 7.01 (1H, s), 5.82-5.72 (1H, m), 5.04 (1H, s), 4.65-4.55 (1H, m), 4.35-4.29 (2H, m), 4.28-4.17 (2H, m), 4.11 (1H, dd, J=13.38, 6.69 Hz), 3.86-3.75 (2H, m), 3.42-3.36 (2H, m), 1.50 (6H, d, J=6.59 Hz), 1.16 (3H, d, J=6.70 Hz)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6](CC2C=CC(OC)=CC=2)[S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.CS(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:8])=[O:9])=[N:2]1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1cc(F)c(-c2cc(F)cc(F)c2)cc1O
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (39.3 mg, 0.062 mmol) in DCM (620 μl) at room temperature was added trifluoromethanesulfonic acid (16.52 μl, 0.186 mmol). The resulting solution was stirred for 1 hour. The solution was then dissolved in 1.5 ml of DMSO and passed through a 0.20 micron filter. An additional 0.5 ml was used to sinse the reaction vial and the solution was passed through the same filter. The resulting DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 5 to 50% MeCN in water (containing 0.1% ammonium hydroxide as an additive), flow rate 40 mL/min to yield N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (10.2 mgs, 32% yield over two steps).1H NMR (500 MHz, DMSO-d6) □=ppm 6.37 (s, 1 H) 6.78 (d, J=9.17 Hz, 1 H) 6.83 (d, J=8.45 Hz, 1 H) 7.17 (d, J=7.20 Hz, 1 H) 7.30-7.43 (m, 4 H) 7.84 (dd, J=8.95, 2.01 Hz, 1 H) 8.19 (d, J=7.88 Hz, 1 H) 8.31 (s, J=8.04 Hz, 1 H) 8.59 (s, 1 H) 10.06 (br. s., 1 H). m/z (ESI) 513.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.C([CH2:20][NH2:21])C1C=CC=CC=1>C(Cl)Cl>[CH3:20][NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: CNc1cc(C)nc2ccccc12
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of 4-chloro-2-methyl-quinoline (4.36 g, 24.5 mmol) and benzylmethylamine (3.13 g, 25.8 mmol) is heated under N2 at 120° C. for 12 h. The residue is dissolved in CH2Cl2 (50 ml) and washed successively with aqueous saturated Na2CO3 (50 mL) and 1M aqueous NaOH (50 ml). The CH2Cl2 layer is evaporated, and the residue is dissolved in MeOH (400 mL) and 4M HCl in dioxane (12 mL). 10% Pd—C (410 mg) are added and the suspension is hydrogenated for 15 h under ambient pressure. The reaction mixture is filtered through a pad of Celite. 1M aqueous NaOH (100 mL) is added and the filtrate is evaporated. The residue is dissolved in water and extracted with CH2Cl2 (3×50 mL). The combined organic extracts are dried and evaporated to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C1CCN2C(=NCCC2)CC1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
To a solution of 4-cyanophenol (655 g, 5.50 mol) in acetonitrile (10 L) at 0° C. under nitrogen was added cuprous chloride (495 mg, 5 mmol, 0.001 eq., 0.1 mol %). DBU (970 mL, 6.51 mol) was added slowly while maintaining the temperature at <5° C. 3-Chloro-3-methyl-1-butyne (570 mL, 5 mole) was added. After stirring for 4 hours at 0° C., the mixture was concentrated at reduced pressure and the residue was partitioned between ethyl acetate (5 L) and 1N HCl (2 L). The organic fraction was washed with 1N NaOH (2×1 L), water (1 L), and brine (1 L). After drying (magnesium sulfate), the solvent was removed at reduced pressure to afford the title compound as a yellow oil (930 g) which was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH2:25])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH:25][C:28]([NH2:29])=[O:27])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)N)ccc2-3)n(C(C)C)n1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)NC(N)=O)ccc2-3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
To a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethylamine (0.120 g, 0.325 mmol) in acetic acid (0.0923 mL) and water (3.45 mL) was added a solution of potassium cyanate (0.132 g, 0.00162 mol) in Water (1.0 mL, 0.056 mol) dropwise. The reaction was stirred at 50° C. overnight, cooled down, filtered, and rinsed with cold water. The crude was precipitated in methanol/water and repurified by reverse-phase HPLC to give 542 as a beige solid (5.5 mg). MS(ESI+) 413.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.12 (dd, J=8.3, 1.5 Hz, 1H), 6.98 (d, J=1.4 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 5.83-5.68 (m, 1H), 5.47 (s, 2H), 4.70 (p, J=7.1 Hz, 1H), 4.44-4.25 (m, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.32 (s, 3H), 1.52 (dd, J=6.5, 1.6 Hz, 6H), 1.32 (d, J=7.0 Hz, 3H)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1c(Cl)cccc1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Cl)c1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-chloro-2-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Li].C[Si](Cl)(C)C.[CH:15]([N:18]([CH:28]([CH3:30])[CH3:29])[C:19](=[O:27])[CH:20]=[CH:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([CH3:17])[CH3:16]>CSC.C(OCC)C>[CH:28]([N:18]([CH:15]([CH3:17])[CH3:16])[C:19](=[O:27])[CH2:20][CH:21]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([CH3:30])[CH3:29]
Reactant: [Li]c1ccccc1OC
Reactant: CC(C)N(C(=O)C=Cc1cccs1)C(C)C
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CSC
Product: COc1ccccc1C(CC(=O)N(C(C)C)C(C)C)c1cccs1
Reaction time: 0.17 h

Procedure:
Copper(I)bromide dimethyl sulfide complex (4.63 g 22.5 mmol) was dissolved in dimethyl sulfide (18 mL), and diethyl ether (15 mL). The solution was cooled to 0° C., whereafter 2-methoxyphenyllithium (41.2) (45 mmol) was added. After 10 min., the temperature was lowered to −78° C. Trimethylsilylchloride (4.89 g, 45.0 mmol) was added, followed by N,N-diisopropyl-3-(2-thienyl)propenamide (41.1) (3.56 g, 15 mmol) in diethyl ether (20 mL). The temperature was allowed to slowly rise to room temperature overnight. The reaction was quenched with saturated NH4Cl (10 mL) and conc. ammonia (10 mL). Diethyl ether (80 mL) was added and the mixture was filtered through Celite. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed once with brine and dried (MgSO4). The solvent was evaporated and the crude product was chromatographed on silica (petroleum ether-ethyl acetate 3:1), affording a yellow oil, 3.75 g (73%): 1H NMR (CDCl3) d 1.12 (t, 6H), 1.29 (t, 6H), 3.02 (m, 2H), 3.4 (br, 1H), 3.80 (s, 3H), 4.03 (m, 1H), 5.26 (t, 1H), 6.8-7.3 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:14][C:15]([NH:13][C:4]1[S:5][C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1)=[O:16])[CH3:22]
Reactant: Cc1nc(N)sc1-c1ccncc1
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Reaction time: 8 h

Procedure:
A stirred solution of 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (prepared according to the method described in European patent specification EP 117082 A2) (0.068 g, 3.56 mmol) in DMF (5 ml) is treated with ethyl isocyanatoacetate (0.043 ml, 3.916 mmol) and the solution is stirred overnight. The solvent is removed in vacuo and the crude product is partitioned between ethyl acetate (50 ml) and water (50 ml). The layers are separated and the aqueous portion is extracted with ethyl acetate (2×50 ml). The combined organic portions are washed with water, dried (MgSO4), filtered and concentrated in vacuo to yield an oil. Trituration with ethyl acetate yields the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1Cc2ccccc2C1
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)NC1Cc2ccccc2C1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (0.096 g, 0.250 mmol) and 2-aminoindane (0.033 g, 0.248 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) was added, and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.092 g (quantitative) of the captioned compound.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[C:12]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2
Reactant: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCC3)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cccc(Nc2ccc3c(c2N)CCC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
3-(4-Nitroindan-5-ylamino)benzonitrile (0.84 g, 3.00 mmol) was dissolved in tetrahydrofuran (84 mL)-methanol (21 mL). To the solution was added water-containing 5% palladium-carbon (0.08 g). The mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. Insoluble was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as yellowish brown crystal (0.75 g, yield 100%).
Reaction SMILES: O.[Cl:2][CH2:3][CH:4]=[O:5].[N+:6]([CH2:8][C:9]([NH2:11])=[O:10])#[C-:7].N12CCCN=C1CCCCC2>CO>[Cl:2][CH2:3][CH:4]1[O:5][CH:7]=[N:6][CH:8]1[C:9]([NH2:11])=[O:10]
Reactant: [C-]#[N+]CC(N)=O
Reactant: O=CCCl
Solvent: CO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)C1N=COC1CCl
Reaction time: 0.5 h

Procedure:
114 g of chloroacetaldehyde monohydrate, and 84 g of isocyanoacetamide were dissolved in 1000 ml of methanol. The mixture was cooled to 0°-3° C. and a solution of 38 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 200 ml of methanol was added with string. At this temperature. stirring was continued for 30 minutes, and, after removal of the cooling bath, for an additional hour. The solvent was removed in vacuo and the residue refluxed twice with 1000 ml each time of ethyl acetate. The combined hot extracts were treated with charcoal, filtered while still hot and evaporated to yield the title compound as a crystalline residue, melting point 110°-112° C. after recrystallization from ethyl acetate.