Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[C:2]=[O:3].[CH3:24][N:25]([CH3:42])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[C:31]([NH2:40])=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:42][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][C:31]=1[NH:40][C:2]([NH:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[O:3]
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(N=C=O)ccc1Oc1ncccc1-c1ccncn1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2N(C)CCCN(C)C)ccc1Oc1ncccc1-c1ccncn1

Procedure:
To 4-(2-(4-isocyanato-2-methylphenoxy)pyridin-3-yl)pyrimidine (93 mg, 0.33 mmol) in toluene (3 mL) was added N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (82 mg, 0.30 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:21])[C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([C:22]#[N:23])=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.CN(C)C=[C:34](C1C=CC(Cl)=CC=1)[C:35](C1C=CC(Cl)=CC=1Cl)=[O:36].COCC(Cl)=O.[H-].[Na+]>CN(C=O)C.C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:10]2[CH:11]=[C:12]3[C:13](=[N:14][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:15]([CH3:21])[C:16](=[O:20])[C:17]([O:18][CH3:19])=[C:22]3[NH:23][C:35](=[O:36])[CH3:34])=[CH:29][CH:28]=1
Reactant: COCC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
N-(6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-cyanopyridin-2-yl)-2-methoxy-N-methylacetamide (368.5 mg, prepared by the reaction of the product of Step A Example 1 with 2-methoxyacetyl chloride using the conditions of EXAMPLE 62 Step A) was combined with THF (5 mL), DMF (0.5 mL) and NaH (48 mg, 60% dispersion in mineral oil). After 15 minutes the reaction was quenched with acetic acid (0.2 mL). The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The concentrated residue was suspended in THF (4 mL), DMF (0.5 mL) and acetyl chloride (0.5 mL). Once LC/MS indicated the acylation was complete, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 502.0 (M+1), 504.00 (M+3); Rt=3.92 min.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:42]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.53 g, 1.06 mmol) in dichloromethane (10 mL) and triethylamine (0.32 g, 3.18 mmol) was added benzoyl chloride (0.156 g, 1.11 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the resulting solid was partitioned between ethyl acetate and water (3×). The organic layer was dried with magnesium sulfate and the solvent removed in vacuo, yielding crude 17, which was them purified using the supercritical fluid chromatography, resulting in 525 mg of pure 1-{(1R,5S)-8-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H-benzimidazole 17 (yield 93%). 1H NMR (400 MHz, CDCl3) δ 7.20 (1H, m), 6.94 (7H, m), 6.82 (4H, m), 6.70 (2H, m), 4.15 (1H, m), 3.75 (1H, m), 3.11 (1H, m), 2.98 (4H, m), 2.93 (1H, m), 2.78 (3H, m), 2.05 (3H, s), 2.04 (2H, m), 1.88 (3H, m), 1.70 (1H, m), 1.59-1.24 (4H, m), 1.14 (2H, m). HRMS m/z (M+H)+Calc 533.3280; (M+H)+Obs 533.3300.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=3)[CH2:38]2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:49][C:46]3[CH:47]=[CH:48][C:43]([N:39]4[CH2:40][CH2:41][CH2:42][CH:37]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:38]4)=[CH:44][CH:45]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C2CCCN(c3ccc(N)cc3)C2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(N5CCN(C)CC5)C4)cc3)nn12
Yield: 45 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.0003480 mol), N,N-Diisopropylethylamine (0.0909 mL, 0.000522 mol) and 4-[3-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.191 g, 0.000696 mol) were dissolved in 1-Methoxy-2-propanol (0.99 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 78.00 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{4-[3-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a lyophilized powder. (M+H)=498.3. 1H NMR (400 MHz, DMSO, d6) δ 9.37 (s, 1H), 8.93 (s, 1H), 7.81 (dd, 1H, J=1.62, 5.96 Hz), 7.67 (d, 2H, J=8.56 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.05 Hz), 7.11 (m, 3H), 6.92 (m, 2H), 3.92 (m, 4H), 3.79 (s, 3H), 3.62 (m, 2H), 3.45 (m, 3H), 3.31 (m, 2H), 3.13 (m, 2H), 2.79 (m, 3H), 1.99 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:22])([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:50][C@H:51]([CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53]>CN(C=O)C.Cl>[CH3:22][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH2:13][O:14][Si:15]([CH3:17])([CH3:16])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:10](=[O:12])[NH:50][C@@H:51]([C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53])[CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: CC(C)(C)OC(=O)NC(C)(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccccc3)C2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 0.25 h

Procedure:
A mixture comprising 2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)-2-methylpropanoic acid (intermediate from step 1) (311 mg, 0.934 mmol) and DIPEA (0.652 ml, 3.73 mmol) in DMF (5 mL) was treated with a solution of ®T3P (50% in EtOAc) (1.090 ml, 1.867 mmol) dropwise at room temperature. The resulting solution was stirred for 15 minutes, then 7-((R)-2-amino-3-(benzyloxy)propanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (intermediate from step 3) (500 mg, 0.934 mmol) in DMF (1 mL) was added dropwise at room temperature. The reaction mixture was stirred for 20 hours. The reaction mixture was diluted with 0.1M HCl (10 mL) and extracted with DCM (3×10 mL). The combined organic portions were washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), water (10 mL) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-70% EtOAc/iso-hexane afforded the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](O)=[O:13].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12]([Cl:25])=[O:13]
Reactant: C#CCOc1c(F)cc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1c(F)cc(C(=O)Cl)cc1F

Procedure:
To 17 ml of toluene were added 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid, 1 ml of thionyl chloride and 10 mg of DMF, and the mixture was heated under reflux for 4 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain 1.9 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:13]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(NCc2ccc(Cl)cc2)cc1)N1CCN(c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1)N1CCN(c2ccccc2)CC1
Reaction time: 18 h
Yield: 125.6 %

Procedure:
To a stirred solution of [4-(4-chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone (30 mg, 0.07 mmol) and phenylsulfonyl chloride (14.2 μl, 0.11 mmol) in anhydrous dichloromethane (1 ml) was added pyridine (7.2 μl, 0.09 mmol) and the reaction was stirred at ambient for 18 hours. PS-trisamine (32 mg, 0.13 mmol) was added and the mixture was agitated for 3 hours then filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (48 mg, 98% yield). HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 547 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(F)c3F)s1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Temperature: 120 °C
Yield: 18.9 %

Procedure:
A mixture of tert-butyl 2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (68 mg, 0.119 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.179 mmol) in dioxane (1 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (38 mg, 0.358 mmol) in water (0.25 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as an off-white solid. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified) to afford he title compound as a white solid (11 mg, 19% yield). MS m/z 489.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.18 (s, 2H), 7.85 (ddd, J=8.6, 6.7, 1.8 Hz, 1H), 7.70 (ddd, J=8.7, 7.0, 1.8 Hz, 1H), 3.91 (s, 4H), 3.28-3.31 (m, 4H), 1.74 (t, J=5.6 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:22](=[O:24])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NCc1ccccc1
Yield: 71 %

Procedure:
The title compound (0.22 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076 g, 0.71 mmol) by an analogous procedure to that described in example 32. mp : 92-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([O:19][CH:20]([CH3:24])[C:21](Cl)=[O:22])(=[O:18])[CH3:17]>CC(C)=O>[C:16]([O:19][CH:20]([CH3:24])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:22])(=[O:18])[CH3:17]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: CC(C)=O
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 88.5 %

Procedure:
20.3 g (100 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 18.0 g (120 millimoles) of 2-acetoxypropionyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 28.1 g (88.6%) of 6-[p-(2-acetoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 198°-200° C. (dimethylformamide/water).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13])=[O:32]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 33.3 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (40.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 492; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, m), 7.88-7.84 (2H, m), 7.51-7.49 (1H, m), 7.37-7.28 (2H, m), 7.19-7.18 (1H, m), 4.18-4.15 (2H, m), 4.11-4.09 (2H, m), 3.03 (3H, s), 2.87 (3H, s), 1.29-1.23 (3H, t), —NH proton signal was not observed.
Reaction SMILES: CO.[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:29]#[CH:30])([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.[Fe]>[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[NH2:26])([C:29]#[CH:30])[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 735 ml of methanol and 51.7 g of 1-N-phenoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added a solution of 51 ml of concentrated hydrochloric acid in 206 ml of water. To the stirred mixture was added, in aliquots, 80.2 g of iron (reduced, electrolytic). The mixture was stirred 2 hr, heated to 45° for 1 hr and allowed to cool to room temperature. The mixture was poured into ice/water, extracted twice with dichloromethane, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on a Waters Prep 500 High Pressure Liquid Chromatograph (1×500 cc silica gel: eluent: 0.5 methanol/dichloromethane). Concentration of the appropriate fractions provided an oil, which crystallized on standing to provide 15.7 g (33%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 125°-127°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([NH:15][CH3:16])=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1.[Na].Cl.CO>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([NH:15][CH3:16])=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1
Reactant: CNC(=O)c1c(C)nc2cc(OC)ccn12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)nc2cc(O)ccn12
Temperature: 120 °C

Procedure:
To a solution of 7-methoxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide (985 mg, 4.49 mmol) in DMF (20 ml) was added sodium thioethylate (80% pure, 1.86 g, 18 mmol) and the mixture heated to 120° C. for 2 hours. After cooling to ambient temperature, the reaction was neutralized to pH 6 with 1N HCl and concentrated in vacuo. The residue was dissolved in MeOH/H2O, pre-absorbed onto SiO2, and purified by flash chromatography (eluting with 90/10/1-80/20/5, DCM/MeOH/cNH3) to yield the crude product as a yellow solid, which was titrated with MeOH to yield 7-hydroxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide 111-B, 700 mg, 78%, as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5]=1[CH3:31])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[C:27]([NH:26][C:24]([NH:23][C:6]1[C:5]([CH3:31])=[C:4]([CH:1]([OH:3])[CH3:2])[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]=1[CH3:22])=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(=O)c1c(C)c(NC(=O)NC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(NC(=O)NC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 3 h
Yield: 15.9 %

Procedure:
To a solution of N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(tert-butyl)urea (718 mg, 1.7 mmol) obtained in Example 204 in methanol (10 mL) was added sodium borohydride (64.3 mg, 1.7 mmol) at 0° C., and the resulting mixture was stirred for 3 hours. The reaction solution was diluted with water and the product was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 115 mg (yield: 16%) of the title compound having high polarity of two isomers. Melting point: 212-214° C. (ethyl acetate-hexane).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1>C(O)(C)C.C1COCC1>[NH2:1][C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1
Reactant: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1(O)CC(c2nc(I)c3c(N)nccn23)C1
Temperature: -78 °C

Procedure:
A solution of 2M ammonia in isopropanol (80 mL) and THF (5 mL) was added to 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.77 g, 7.62 mmol) in a Parr pressure reactor. The mixture was cooled to at −78° C. then ammonia gas was bubbled into the solution for 4-6 min. The reactor was sealed then heated at 110° C. for 15 h. The solvent was then removed in vacuo and the residue purified by chromatography over silica gel eluting with 7% MeOH in DCM to afford desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H), 2.32-2.51 (m, 4 H), 3.33-3.52 (m, 1 H), 6.61 (br.s., 2 H), 7.03 (d, J=5.05 Hz, 1 H) and 7.62 (d, J=5.05 Hz, 1 H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N+:20]([O-:21])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ONCc1ccccc1
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: O=S(=O)(O)c1ccc(C=[N+]([O-])Cc2ccccc2)o1
Yield: 82 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-benzylhydroxylamine, the title compound was prepared in 82% yield as the sodium salt, m.p. 223.7° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)([O-:3])=[O:2].CO.C(NCC)C>C(=O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(NC[C@H]2CCCOC2)c([N+](=O)[O-])c1
Agent: O=C=O
Solvent: CO
Solvent: CCNCC
Product: NS(=O)(=O)c1ccc(NC[C@@H]2CCCOC2)c([N+](=O)[O-])c1

Procedure:
The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an AD column (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1% diethylamine methanol in CO2 over 15 minutes (oven temperature: 40° C.; flow rate: 40 mL/minute) to provide the title compound.