Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[CH3:13]OC(N(C)C)OC>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(Br)c2cc[nH]c2c1
Yield: 36.1 %

Procedure:
1-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and (dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refluxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refluxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39%) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.C(N(CC)CC)C.CC([Si](C)(C)[O:35][C@@H:36]([C@@H:45]([CH3:49])[C:46](=[O:48])[CH3:47])[C@@H:37]([CH3:44])[C:38](N(OC)C)=[O:39])(C)C.[NH2:52][C:53]([O:55][C@@H:56]([C@@H:91]([CH3:96])/[CH:92]=[CH:93]/[CH:94]=[CH2:95])[C@@H:57]([CH3:90])[C@H:58]([O:82][Si](C(C)(C)C)(C)C)[C@@H:59]([CH3:81])[CH2:60]/[C:61](/[CH3:80])=[CH:62]\[C@H:63]([CH3:79])[C@@H:64]([O:71][Si](C(C)(C)C)(C)C)[C@@H:65]([CH3:70])/[CH:66]=[CH:67]\[CH:68]=[O:69])=[O:54]>C(OCC)C>[CH3:49][C@@H:45]1[C@H:36]([OH:35])[C@@H:37]([CH3:44])[C:38](=[O:39])[O:48][C@H:46]1[CH2:47][C@H:68]([OH:69])/[CH:67]=[CH:66]\[C@@H:65]([C@H:64]([OH:71])[C@H:63](/[CH:62]=[C:61](\[CH2:60][C@@H:59]([C@@H:58]([OH:82])[C@@H:57]([C@@H:56]([O:55][C:53]([NH2:52])=[O:54])[C@H:91](/[CH:92]=[CH:93]\[CH:94]=[CH2:95])[CH3:96])[CH3:90])[CH3:81])/[CH3:80])[CH3:79])[CH3:70]
Reactant: C=C/C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C=O
Reactant: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(C)=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.18 g (6.79 mmol, 10 equiv.) of (+)-β-chlorodiisopinocamphenylborane in 4 mL of diethyl ether at 0° C. is added 1.04 mL (11 equiv., distilled over calcium hydride) of triethylamine and then a solution of 2.25 g (6.79 mmol, 10 equiv.) of the compound of Example 1 in 3 mL of diethylether. After stirring for 2 hours at 0° C., the mixture is cooled to −78° C., after which time a pre-cooled (−78° C.) solution of 450 mg (0.679 mmol) of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15E)-13-[(amino-carbonyl)oxyl]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenal in 4 mL of diethylether is added via cannula. After the resultant mixture is maintained at a temperature of −78° C. for 3 hours, it is transferred to a freezer (−27° C.) for 16 hours. The reaction is then quenched with 8 mL of methanol (the pH of which is adjusted to 7 with 12 mL of buffer solution) and 4 mL of 50% hydrogen peroxide solution at 0° C. After stirring for 2 hours at 25° C., the organic layers are separated. The aqueous layer is then extracted five times with 25 mL portions of dichloromethane. The combined organic layers are then dried over magnesium sulfate, concentrated using a rotary evaporator and chromatographed (Biotage, silica gel, gradient 10-30% ethyl acetate/hexane) to yield the desired compound as a colorless, highly viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:30])[C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:38]([O:40][CH2:41][CH3:42])=[CH2:39])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([O:40][C:38]([C:2]1[CH:3]=[C:4]([F:30])[C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1)=[CH2:39])[CH3:42]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)[C@H]1CCN(c2cnc3ccc(Sc4nnc5c(F)cc(Br)cn45)cc3c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(F)c2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 6.98 %

Procedure:
The solution of (85.1) (175 mg, 0.359 mmol) and PdCl2(PPh3)2 (37.8 mg, 0.054 mmol) in DMF (10 ml) was bubbled by N2 for 5 min. tributyl(1-ethoxyvinyl)stannane (195 mg, 0.539 mmol) was added. The reaction tube was flushed by N2 for 5 min again and sealed. The sealed-tube was stirred at 90° C. for 2 h. Then the reaction was continued at 110° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by column chromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 10%) to afford the target product (40 mg, 30% pure, yield 6.98%). LCMS (method A): [M+H]+=479.1, tR=1.92 min.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:19]Br>O1CCCC1.ClCCl>[Br:19][C:4]([CH3:3])([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: BrBr
Reactant: CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride (1.7g, 80% dispersion in oil) in tetrahydrofuran (60 ml) under an atmosphere of nitrogen was added di-t-butyl methylmalonate (11.52g). The mixture was stirred at 60°-70° for 1.5 hours to give a clear solution. This solution was cooled to -25°, and to it was rapidly added a solution of bromine (2.6 ml) in dichloromethane (30ml). The solution was allowed to warm to ambient temperature, then concentrated. The residue in ether was washed with water, dried, and fractionally distilled under reduced pressure to give the title compound b.p. 78°-86°/1.0 mm Hg, (7.56g, 49%); νmax (CHBr3) 1730cm-1 (CO2But); τ (CDCl3) values include 8.05 (s, C(CH3)3) and 8.53 (2s, CH3 and C(CH3)3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10](Cl)[CH3:11])([CH3:4])([CH3:3])[CH3:2].CN(C)P(N(C)C)(N(C)C)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([O:5][C:6]([CH:7]1[CH:10]([CH3:11])[CH2:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cl)CN(CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)C1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To a solution of an optically-active compound of [benzyl-(2-chloropropyl)-amino]acetic acid tert-butyl ester (60.0 g) and hexamethyl phosphoramide (36.0 ml) in tetrahydrofuran (360 ml) cooled to −72° C. was added dropwise lithium hexamethyl disilazide (1.0M tetrahydrofuran solution, 242 ml) over 18 minutes, and the mixture was warmed to 0° C. over 80 minutes. To the reaction mixture were sequentially added saturated aqueous ammonium chloride solution (300 ml) and water (400 ml), and the mixture was extracted with ethyl acetate (500 ml). The organic layer was sequentially washed with water (700 ml) and saturated aqueous sodium chloride solution (500 ml), and the separated aqueous layer was extracted with ethyl acetate (300 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1 to 4/1) to give the titled compound (50.9 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH:21]3[S:27][CH2:26][CH2:25][NH:24][C:23](=[O:28])[CH2:22]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.ClCCl.CS(C)=O>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH:21]3[S:27](=[O:39])[CH2:26][CH2:25][NH:24][C:23](=[O:28])[CH2:22]3)[N:11]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CC(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)SCCN1
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CC(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of N-(4-fluorobenzyl)-8-hydroxy-5-(5-oxo-1,4-thiazepan-7-yl)[1,6]naphthyridine-7-carboxamide (Example 141) (0.22 g, 0.52 mmol) in DMF (25 mL), a solution of 3-chloroperbenzoic acid in dichloromethane (0.57 mmol, 0.129 g/mL) was added and stirred at room temperature for 2 hours. The product mixture was treated with DMSO (1 mL), diethyl ether (200 mL), and cooled in an ice bath. The resultant precipitate was filtered, dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:12][CH2:11][CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)\[CH3:19])[CH3:14]
Reactant: OCC1COc2ccccc2O1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)OCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.2 %

Procedure:
To a stirred mixture of (2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (1.01 g, 5.90 mmol) and ethyl-2-butynoate (820 mg, 7.08 mmol) in tetrahydrofuran (15 mL) was added tri-n-butylphosphine (0.25 g, 1.18 mmol). The mixture was stirred at room temperature for 1.5 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 50% ethyl acetate/hexanes) to afford (E)-3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-but-2-enoic acid ethyl ester (660 mg, 40%) as a colorless oil: LR-ES-MS m/z calculated for C15H18O5 [M]+ 278, observed [M+H]+ 279.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[NH2:18][C:10]1[CH:11]=[C:12]([CH2:15][C:16]#[N:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: N#CCc1ccc(OCc2ccccc2)c(N)c1
Yield: 76.7 %

Procedure:
In the presence of Raney nickel, 53.6 g of (4-benzyloxy-3-nitrophenyl)acetonitrile in 1.2 1 of methanol is hydrogenated until 12.2 1 of hydrogen has been absorbed. The crude product obtained after removing the catalyst by filtration and after evaporation is purified by chromatography on silica gel with cyclohexane/ethyl acetate (1:1), thus obtaining 36.5 g of (3-amino-4-benzyloxyphenyl)acetonitrile as an oil.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([C:9]1[C:10]([CH:17]([CH3:19])[CH3:18])=[C:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH:13]=1)[CH3:8].S(C1C=CC(C)=CC=1)(O[CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=O)=O.O>C1COCC1>[CH3:27][N:26]([CH2:25][CH2:24][C:13]1[CH2:12][C:11]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:17]([CH3:19])[CH3:18])[C:9]=1[CH:7]([CH3:6])[CH3:8])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CC(C)C1=CCC(C(C)C)=C1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1=C(C(C)C)C(C(C)C)=C(CCN(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a dry 500 mL three-necked flask with a magnetic stirrer, a solution of 62.5 mL of n-butyllithium (1.6M in n-hexane; 100 mmol) was added under a dry nitrogen atmosphere to a solution of 19.2 g (100 mmol) of tri-(2-propyl)cyclopentadiene in 250 mL of THF at -60° C. After heating to room temperature (in approximately 1 hour) stirring continued for a further 2 hours. After cooling to -60° C., a solution of (dimethylaminoethyl) tosylate (105 mmol) prepared in situ was added over a period of 5 minutes. The reaction mixture was heated to room temperature, followed by overnight stirring. The degree of conversion of the reaction was monitored by GC. After addition of water, the product was extracted with petroleum ether (40-60° C.). The combined organic layer was dried (Na2SO4) and evaporated under reduced pressure. The conversion was greater than 95%. 30% of the product is geminally substituted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[CH3:8].NC1C=C(C=CC=1C)OCC#N.CC1C=CC(OCC#N)=CC=1[N+]([O-])=O>>[NH2:9][C:6]1[CH:5]=[C:4]([CH2:12][C:13]#[N:14])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(CC#N)cc1[N+](=O)[O-]
Agent: Cc1ccc(OCC#N)cc1N
Agent: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Product: Cc1c(N)cc(CC#N)cc1Cl

Procedure:
(3-Amino-5-chloro-4-methylphenyl) acetonitrile was prepared from (3-chloro-4-methyl-5-nitrophenyl) acetonitrile in a manner similar to that described in Example 2 for the preparation of (3-amino-4-methylphenoxy) acetonitrile from (4-methyl-3-nitrophenoxy) acetonitrile.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1.I[CH3:12]>C1COCC1>[CH3:12][O:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1
Reactant: COC(=O)C1(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(OC)CC1
Reaction time: 0.25 h

Procedure:
NaH (738 mg, 18.44 mmol; 60% dispersion in oil) was added to a solution of methyl 1-hydroxycyclopropanecarboxylate (1.83 g, 14.18 mmol) in anhydrous THF (15 mL) cooled on an ice bath. The mixture was stirred for 15 minutes then iodomethane (3.22 g, 1.42 mL, 22.69 mmol) was added slowly, and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was quenched with ammonium chloride and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure to give methyl 1-methoxycyclopropanecarboxylate. An aqueous 6N NaOH solution (4 mL) was added to a solution of methyl 1-methoxycyclopropanecarboxylate (1.08 g, 8.3 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 18 hours, then acidified with aqueous 6N HCl and extracted with EtOAc (3×15 mL) The combined organic layer was dried over MgSO4, filtered and concentrated to give 1-methoxycyclopropanecarboxylic acid (892 mg, 54% yield) as an oil. 1H NMR (400 MHz, (CD3)2SO) δ 12.40 (br s, 1H), 3.30 (s, 3H), 1.15-1.10 (m, 2H), 1.08-1.04 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.O.C1COCC1>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:28]4[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: COc1cc2ncn(-c3nc(-c4ccc(C)cc4)c(C(=O)O)s3)c2cc1OC
Temperature: 100 °C
Yield: 53.4 %

Procedure:
To a solution of 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol), 4-methylphenylboronic acid (20.4 mg, 0.15 mmol) in ethylene glycol dimethyl ether (1 ml) was added Na2CO3 (2M, 100 μL, 0.2 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) (4 mg, 0.005 mmol). The mixture was heated to 100° C. for 3 hrs. The solvent was evaporated and 2 ml water was added. It was then extracted with 2×3 ml EtOAc. The combined organics were concentrated in vacuo. To this crude was added THF (0.5 ml), water (0.5 ml), methanol (0.2 ml) and NaOH (20 mg, 0.05 mmol). The mixture was heated to 60° C. for 3 hrs. The solvents were evaporated and the crude was purified by prep-HPLC to afford 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-p-tolyl-thiazole-5-carboxylic acid (21.1 mg, 53%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.57 (br.s., 1H); 8.82 (s, 1 H); 7.83 (m, 3 H); 7.39 (s, 1 H); 7.31 (d, 2 H); 3.86 (s, 3 H); 3.85(s, 3 H), 2.39 (s, 3H). MS m/z 396 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:30]4)=[C:21]([C:22]#[N:23])[CH:24]=3)=[O:15])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: O=C(O)c1ccn(-c2ccc(Cl)cc2)c1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(Cl)cc3)c2)ccc1N1CCN(CCO)CC1
Yield: 27.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)pyrrole-3-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.67 g), the title compound (1.1 g) was obtained, melting point: 196° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[N:39][CH:40]=2)O1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:40]=[N:39][C:38]([N:41]3[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.216 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (94 mg, 0.324 mmol). The product obtained from HPLC purification was treated with a saturated solution of NaHCO3, and solids that crashed out were filtered. The product was evaporated from MeOH, triturated from ether and then CH3CN. After drying in vacuum oven overnight, the final product was collected as a white solid (87 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.59-8.67 (m, 2H) 8.54 (s, 1H) 8.35 (s, 1H) 8.02-8.09 (m, 2H) 7.84 (s, 1H) 6.94 (d, J=9.09 Hz, 1H) 5.89 (s, 1H) 5.14 (dt, J=13.07, 6.47 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.41-3.47 (m, 4H) 3.17 (s, 1H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H). LC-MS (ES) m/z=500.4 [M+H]+ Note: some piperinzyl proton atoms hidden under water peak.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[NH:12][CH2:13][CH2:14][S:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCS
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2NCCS2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of p-methoxybenzaldehyde (1.81 g, 13.3 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 18 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified by addition of solid sodium carbonate (0.3 g) causing the product to precipitate out of solution. The precipitate was filtered, washed carefully with water (3×20 ml) and dried in a vacuum desiccator to give 2-(4-methoxyphenyl)-1,3-thiazolane (5) as a white solid (0.55 g, 69%), mp 94-95° (lit mp, 93-94°). 1H nmr (CDCl3, 300 MHz) 2.51, s, NH; 3.05-3.20, m, H4,4,5; 3.64, m, H5; 3.80, s, OMe; 5.23, s, H2; 6.87, d (8.7 Hz), H3′,5′; 7.44, d (8.7), H2′,H6′. ESI (+ve) MS m/z 196 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CN(C)C=CC(=O)c1ccsc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccsc3)ccnc12

Procedure:
As for Example 2, 3.10 g. of 3-amino-4-carboethoxypyrazole is heated at reflux temperature for 10 hours with 3.62 g. of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 4.40 g. of the product of the example as tan crystals, m.p. 129°-130° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:27]#[C:28][C:29]5([CH3:33])[CH2:32][O:31][CH2:30]5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[ClH:35].C(OCC)(=O)C>CC#N.C(=O)(O)[O-].[Na+]>[NH2:26][C:23]1[O:24][CH2:25][C@:21]2([C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:27]#[C:28][C:29]([CH2:32][Cl:35])([CH3:33])[CH2:30][OH:31])[CH:19]=3)[O:14][C:11]3[C:10]2=[CH:9][C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=3)[N:22]=1
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2)(CO)CCl
Temperature: 50 °C
Yield: 53.6 %

Procedure:
To a slurry of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (500 mg, 1.13 mmol, Example 78) in 10 mL of MeCN was added 10 mL of water followed by 1 mL of 6 N HCl. The resulting solution was heated at 50° C. overnight. The reaction was cooled to rt, diluted with saturated sodium bicarbonate (100 mL) and poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a white solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% DCM to 10:1 methanol in DCM with 0.1% ammonium hydroxide) to provide 4-((S)-2′-amino-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-(chloromethyl)-2-methylbut-3-yn-1-ol (290 mg, 0.606 mmol, 53.6% yield) as a white solid.