Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1F
Reaction time: 0.5 h
Yield: 145.9 %

Procedure:
To a solution of 3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (106 mg, 0.30 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (147 mg, 0.45 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (65 mg, 0.136 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 40:1) to give the title compound as a colorless oil (90 mg, 66%).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C.O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:54])[F:53])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reaction time: 0.83 h
Yield: 103.8 %

Procedure:
To a solution of 500 mg (0.64 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in a mixture of 5 ml ethanol and 5 ml tetrahydrofuran, 12 mg (0.32 mmol) of sodium borohydride was added under ice cooling, and the reaction solution was stirred under ice cooling conditions for 0.83 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and 1 N hydrochloric acid and 1 N sodium hydroxide aqueous solution were added in order, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 0.52 g of the title compound as a white foam (yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[CH3:29][N:30](C=O)C.O>CCOC(C)=O.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.[Fe+2].[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:29]#[N:30])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)CC2)ccc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)CC2)ccc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a 2000 mL flask was charged with 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (40 g, 78.1 Mmol), dppf (3.86 g, 6.96 mmol), Zn(CN)2 (9.6 g, 81.6 Mmol), DMF (360 mL) and H2O (20 mL). The resulting suspension was degassed using N2 for 5 min, followed by addition of Pd2(dba)3 (4.24 g, 4.64 mmol). The reaction mixture was heated under N2 at 90° C. for 2 h (monitor by TLC and LC-MS). After cooling to room temperature, diluted with EtOAc (1500 mL), filtered to remove the precipitate and washed with H2O (1000×2 mL), saturated EDTA.4Na (800 mL×2), brine and dried over Na2SO4. After evaporation of the solvent, ether (150 mL) was added and stirred for 2 h. The resulting solid was filtered to give the desired product 30 g (93%) as light yellow powder. Recrystallization from refluxing CH3CN (160 mL) afforded 26 g (80%) light yellow crystals: mp 183-185° C.; Rt=2.38 min; MS (ES) M+H expect 411.1, found 411.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:14][CH2:13][CH2:12][CH2:11][N:10]3[C:15](=[O:17])[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:71]1[CH:76]=[CH:75][N:74]=[C:73]([S:77][CH3:78])[N:72]=1>C1(C)C=CC=CC=1>[CH3:78][S:77][C:73]1[N:74]=[C:75]([N:14]2[CH2:13][CH2:12][CH2:11][N:10]3[C:15](=[O:17])[CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[C:9]23)[CH:76]=[CH:71][N:72]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2
Reactant: CSc1nccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(N2CCCn3c2cc(-c2ccccc2)cc3=O)n1
Temperature: 70 °C

Procedure:
To a mixture of 8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (1.86 g, 8.23 mmol), sodium tert-butoxide (1.6 g, 16 mmol), BINAP (0.15 g, 0.207 mmol), and Pd (OAc)2 (55 mg, 0.2 mmol) was added toluene (20 mL) and 4-chloro -2-methylthiopyrimidine (1.5 mL, 12 mmol). After purged with N2 for 10 min, the overall mixture was heated at 70° C. for 3 h prior to being cooled to room temperature. The resulting material was diluted with saturated NHCl(aq), water, and DCM. The organic layer was taken and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtrated, and concentrated. Column chromatographic purification (3% MeOH in DCM) of the crude residue afforded the title compound as a yellow solid. MS m/e 351 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:35])([F:34])[C@H:29]([OH:33])[CH2:30][CH2:31]O>ClCCl>[F:27][C:28]([F:35])([F:34])[C@H:29]([OH:33])[CH2:30][CH2:31][I:25]
Reactant: OCC[C@@H](O)C(F)(F)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O[C@H](CCI)C(F)(F)F
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Triphenylphosphine (5.09 g, 19.4 mmol) was dissolved in dichloromethane (66 mL) and treated with imidazole (1.33 g, 19.5 mmol) and iodine (4.92 g, 19.4 mmol), respectively, to give an orange suspension. A solution of (R)-4,4,4-trifluoro-1,3-butanediol (2.34 g, 16.2 mmol) in dichloromethane (18 mL) was added to the suspension and stirred for 30 minutes. The reaction mixture was placed on a silica gel flash column and eluted with 100% dichloromethane to give the product as a pale purple oil (3.30 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.Cl.[C:31]([BH3-])#N.[Na+].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCOCC1.CCOCC.CO>[NH2:1][C:2]1[C:7]([CH2:8][O:9][CH3:31])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C=O)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of tert-butyl 3-[2-amino-3-formyl-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.100 g, 0.252 mmol) in 1,4-dioxane (2.0 ml) under an argon atmosphere was added a HCl solution of 1,4-dioxane (4N, 2.0 mL), and the stirring was continued at room temperature for 1 hr. The mixture was diluted with Et2O, and the supernatant was decanted. The precipitates were washed twice with Et2O, and dried under reduced pressure to give a pale yellow solid, which was then dissolved in methanol (2.0 mL). The mixture was allowed to cool with ice-water bath. Then sodium cyanoborohydride (0.047 g, 0.76 mmol) was added to the mixture under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of methylene chloride (2.0 mL) and THF (2.0 mL). To the mixture was added triethylamine (0.140 mL, 1.006 mmol) followed by di-tert-butyl dicarbonate (0.110 g, 0.503 mmol), and the stirring was continued for 2 hrs. The resulting mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 2:1) to give tert-Butyl 3-[2-amino-6-(2-hydroxyphenyl)-3-(methoxymethyl)-4-pyridinyl]-1-piperidinecarboxylate. (0.033 g, yield; 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]3[S:12][C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([NH:8][CH2:9]3)[C:6]=2[CH:19]=1.S[CH2:21][C:22](O)=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22](=[O:23])[CH2:21][S:12][CH:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C1(c3ccccc3)NCC(N2)S1
Reactant: O=C(O)CS
Solvent: C1CCOC1
Product: O=C1CSC2CN=C(c3ccccc3)c3cc(Cl)ccc3N12

Procedure:
A solution of 7-chloro-2,3,4,5-tetrahydro-5-phenyl-2,5-epithio-1H-1,4-benzodiazepine (500 mg) in THF was treated slowly with excess mercaptoacetic acid (0.5 ml) and stirred and heated under reflux for 16 hours. The cooled solution was washed with aqueous sodium carbonate, dried, evaporated, and the oily residue taken up in ether. The desired product was re-crystallized from methylene chloride/methanol and was obtained as pale yellow crystals, m.p. 228°-230°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[Br:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2Br)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3Br)CC2)cc1
Yield: 238.5 %

Procedure:
0.54 g (0.002 mol) of 1-(2-bromo-benzyl)-piperidin-4-ol and 1.23 ml (0.0088 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.463 g (60%) 1-(2-bromo-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: N1CCC[C@H]1C(OC(C)(C)C)=O.CCN(CC)CC.[C:20]1([CH2:26][CH2:27][S:28]([N:31]2[CH2:42][CH2:41][CH2:40][C@H:32]2[C:33]([O:35]C(C)(C)C)=[O:34])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)=O>C(Cl)Cl>[C:20]1([CH2:26][CH2:27][S:28]([N:31]2[CH2:42][CH2:41][CH2:40][C@H:32]2[C:33]([OH:35])=[O:34])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)CCc1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)CCc1ccccc1

Procedure:
PhCH2CH2SH was treated with Cl2 in a rapidly stirred mixture of CHCl3 and H2O, and then the CHCl3 layer was washed with 5% NaHSO3 and sat. NaCl, dried with MgSO4, filtered, and concentrated to give PhCH2CH2SO2Cl. This product was treated with Pro-OtBu and Et3N in CH2Cl2 to give, after aqueous workup, PhCH2CH2SO2-Pro-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give PhCH2CH2SO2-Pro-OH. This product was treated with HCl.Phe-OtBu, EDAC, HOBT, and Et3N in CH2Cl2 to give, after aqueous workup and flash chromatography, PhCH2CH2SO2-Pro-Phe-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give the title compound as a clear oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:9][C:8]2[N:10]=[CH:11][C:12]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1.[Cl:19][C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]=1[CH2:29][NH:30][CH3:31]>>[ClH:19].[Cl:19][C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]=1[CH2:29][N:30]([CH3:31])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:12]1[CH:11]=[N:10][C:8]2[NH:9][C:3](=[O:2])[CH2:4][NH:5][CH2:6][C:7]=2[CH:13]=1
Reactant: CNCc1oc2ccccc2c1Cl
Reactant: O=C(O)C=Cc1cnc2c(c1)CNCC(=O)N2
Agent: Cl
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)CNCC(=O)N2
Yield: 34.1 %

Procedure:
According to the method of example 43d, 3-(2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid hydrochloride (152 mg, 0.5 mmol) and (3-chloro-benzofuran-2-ylmethyl)methylamine (108 mg, 0.55 mmol) were coupled to yield crude product which was triturated with methanol and ether several times and dried. The residue was re-solvated in methylene chloride (5 mL) and a solution of 2M HCl in ether (2 mL) was added to precipitate the hydrogen chloride salt. The precipitate was collected by filtration and dried to give the title compound (42 mg, 19%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.38-7.68 (m, 6H), 4.88-5.08 (rotamers, 2s, 2H), 3.90 (s, 2H), 3.63 (s, 2H), 3.31 (s, 3H); MS (ESI) m/e 411 (C21H19ClN4O3+H)+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:15]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCCl
Product: COc1ccc(C(=O)CCCCCl)cc1

Procedure:
Using anisole (15.0 g) and 5-chlorovaleryl chloride (18.0 ml) according to the same method as that of Reference. Example 1, the title compound was obtained as colorless crystals (27.3 g) having a melting point of 67 to 68° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)CCC>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:12][CH:13]2[CH:17]([OH:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[N:7]=1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(N(C)C)nc(NC2CN(C(=O)OC(C)(C)C)CC2O)n1
Yield: 85.7 %

Procedure:
2-Chloro-4-dimethylamino-6-methylpyrimidine (3.5 g), t-butyl (3RS,4RS)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.5 g), N,N-diisopropylethylamine (5.3 mL), and n-butanol (10 mL) were stirred at 120° C. for 8 days. To the reaction mixture were added chloroform and saturated aqueous sodium hydrogencarbonate to separate the layers. The aqueous layer was extracted with chloroform, then the organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9:1) to obtain t-butyl (3RS,4RS)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (5.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[CH:20]=1)([O-:9])=[O:8].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:15]1[C:14]2[CH:20]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=2[O:19][CH2:18][CH2:17][CH2:16]1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 49.2 %

Procedure:
Powdered and flame dried potassium carbonate (1.52 g, 11 mmol, 1.1 eq.) was placed in a round bottom flask together with 60 mL of anhydrous dimethylformamide and kept under inert atmosphere. 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.942 g, 10 mmol, 1 eq.) was dissolved in 20 mL of anhydrous DMF and added to the reaction mixture. The reaction was heated to 120° C. under reflux condenser for 1 hour and then solution of ethyl bromoacetate (3.34 g, 2.22 mL, 20 mmol, 2 eq.) in 5 mL of dry DMF was added dropwise to the hot solution. The reaction mixture was then heated to 120° C. for an additional 12 hours. When cooled, the DMF was removed on the rotary evaporator, and diluted with 100 mL of water. The aqueous phase was washed (3×) with 50 mL portions of methylene chloride. The methylene chloride extracts were combined and washed with water and brine and dried over magnesium sulfate. Crude material (3.018 g) was chromatographed on a large Biotage column in 20% ethyl acetate/hexanes. 1.38 g (50% yield) of pure material (bright yellow crystalline powder) was collected. LC MS: AP+281, AP−280.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:2].N.C([N:32](C(C)C)CC)(C)C>CO>[NH2:32][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:23])[N:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12
Agent: N
Solvent: CO
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one (example 74e), ammonia in methanol, and DIEA (diisopropylethylamine) to give 2-amino-5-[1-(4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 378 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:18])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 60 °C

Procedure:
To a solution of 6-bromo-1H-indazole-3-carboxylic acid (1.5 g, 6.22 mmol) in methanol (25 mL) was added thionyl chloride (2.26 ml, 31.12 mmol). The mixture was heated at 60° C. for 1 hr. The reaction mixture was cooled and concentrated in vacuo. The crude residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate: 1H NMR (500 MHz, CDCl3) delta 4.08 (3H, s), 7.44 (1H, d, J=8.6 Hz), 7.89 (1H, s), 8.09 (1H, d, J=8.7 Hz), 11.70 (1H, s); LC-MS: m/z=+254.85/256.75 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:27][C:18]2=[C:19]3[N:24]([N:25]=[C:17]2[CH2:16]1)[CH:23]=[C:22]([Br:26])[CH:21]=[N:20]3)=O)(C)(C)C>>[ClH:1].[Br:26][C:22]1[CH:21]=[N:20][C:19]2[N:24]([N:25]=[C:17]3[CH2:16][NH:15][CH2:27][C:18]3=2)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nn3cc(Br)cnc3c2C1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc2c3c(nn2c1)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (35 mL; 140 mmol; 23.7 eq.) was added to 6-bromo-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (2 g; 5.9 mmol; 1 eq.) and the resulting mixture was stirred at room temperature for 18 hours. The precipitate was filtered off, washed with Et2O and dried to afford the title compound (1.56 g, 96%) as beige solid. 1H NMR (DMSO-d6) δ 10.61 (br s, 2H), 9.68 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 4.56 (s, 4H). UPLC/MS: (MS+) 239.1 and 241.1 ([M+H]+).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[C:16]([F:17])=[C:15]2[C:10]([C:11](=O)[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:14]2)=[CH:9][CH:8]=1>C(#N)C>[Br:3][C:11]1[C:10]2[C:15](=[C:16]([F:17])[C:7]([Cl:6])=[CH:8][CH:9]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cc(-c2ccccc2)[nH]c2c(F)c(Cl)ccc12
Solvent: CC#N
Product: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Phosphorus oxybromide (19 g, 0.066 mole), 7-chloro-8-fluoro-2-phenyl-1H-quinolin-4-one (6.2 g, 0.022 mole) and acetonitrile (40 mL) were combined in a 150 mL pressure bottle with a magnetic stir bar. The flask was heated at 100° C. and stirred overnight. Heat was removed, and an ice-water bath was installed. After 10 minutes, the bottle was opened, and water (60 mL) was added to the cooled stirring reaction. The quenching was exothermic to ca. 50° C. After stirring 10 minutes, a nice, filterable solid had formed, however, the reaction was extracted with 100 mL, then 3×50 mL methylene chloride. The extracts were combined, washed with saturated sodium bicarbonate solution (100 mL), and suction filtered through a small pad of silica gel, rinsing with methylene chloride. The filtrate was concentrated in vacuo, and put under high vacuum at 45° C. for 1 h to afford the crude product, which was recrystallized from 100 mL of ethanol, suction filtered to collect, and washed with ethanol. The purified product was vacuum oven dried for 1 h at 45° C. to afford the title compound as a white solid. A second crop was taken. The mother liquor was concentrated then chromatographed on silica gel with hexanes/methylene chloride 1:1 and combined with the second crop to afford additional material; 1H NMR (CDCl3, 400 MHz) δ 7.49-7.55 (m, 4H), 7.87-7.90 (dd, 1H, J=1.7 Hz & J=8.9Hz), 8.15-8.18 (dd, 2H, J=1.5 Hz & J=7.9 Hz), 8.21 (s, 1H); HPLC tR=4.15 min (OpenLynx, nonpolar—5 min).