Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]=[O:20])=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1cc(/C=C/C=O)ccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(/C=C/CO)ccc1Cl
Reaction time: 3 h

Procedure:
A solution of the compound (631 mg, 2.00 mmol) of Example 20-3 in tetrahydrofuran (4.0 ml) and methanol (2.0 ml) was stirred at ice cooling. Thereto was dropped an aqueous solution (0.20 ml) of sodium borohydride (38.0 mg, 1.00 mmol) under ice cooling and the mixture was stirred for 3 hour at the same temperature. Thereto was added 10% aqueous citric acid solution and the solution was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogencarbonate, solution and an aqueous saturated sodium chloride solution in the order, and dried over sodium sulfate. The solvent was removed to give the subject compound as a colorless oil (651 mg, quantitatively).
Reaction SMILES: I[C:2]1[CH:7]=C[C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:45]4C=[CH:49][C:48](C)=[CH:47][CH:46]=4)=[C:15]4[N:44]=[C:18]([C:19](C5C=CC=CC=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6C=[CH:34][C:33](C)=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.I[C:53]1[CH:58]=[CH:57][C:56](SC(=O)C)=[CH:55][CH:54]=1.[CH3:63][C:64]1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>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]>[C:63]([C:53]1[CH:54]=[CH:55][C:56]([C:19]2[C:20]3[NH:37][C:23]([C:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:25]4[N:29]=[C:28]([C:8]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:7])=[C:9]5[NH:13][C:12](=[C:14]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:15]6[CH:16]=[CH:17][C:18]=2[N:44]=6)[CH:11]=[CH:10]5)[CH:27]=[CH:26]4)=[CH:22][CH:21]=3)=[CH:57][CH:58]=1)#[CH:64]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Cc1ccc(-c2c3nc(c(-c4ccc(I)cc4)c4ccc([nH]4)c(-c4ccc(C)cc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CC(=O)Sc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C#Cc1ccc(-c2c3nc(c(CCCCC)c4ccc([nH]4)c(CCCCC)c4nc(c(CCCCC)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 24 h

Procedure:
S-Acetylthio-derivatized triple decker (15). Samples of (Pc)Eu(Pc)Eu(E′B-Por) (28) (15 mg, 7.0 μmol), 4-iodo-1-(S-acetylthio)benzene (2.0 mg, 7.0 μmol), Pd2(dba)3 (1.0 mg, 1.1 μmol) and P(o-tolyl)3 (2.5 mg, 8.3 μmol) were added to a Schlenk flask. The flask was evacuated and purged with argon three times. Then deaerated toluene (3 mL) and deaerated N,N-diisopropylethylamine (0.6 mL) were added by syringe. The flask was immersed in an oil bath at 35° C. and stirred under argon. The reaction was monitored by TLC (silica, toluene) and LD-MS. After 24 h, the solvent was removed under vacuum, the residue dissolved in toluene/ether (60:1), and loaded onto a silica gel column packed with the same solvent. Elution with toluene/ether (60:1) afforded the desired product together with trace of unreacted starting material as the first band. The product thus obtained was further purified by a second column chromatography procedure (silica gel, toluene), affording a black solid (15) (3.1 mg, 19%) after removal of the solvent and washing with CH3OH. 1H NMR (CDCl3) δ 1.91 (m, 27H), 2.62 (s, 3H), 3.28 (m, 8H), 4.70-4.80 (m, 3H), 4.98 (d, J=6.6 Hz, 1H), 6.68 (m, 4H), 6.94 (d, J=6.6 Hz, 1H), 7.54 (m, 1H), 7.71 (m, 1H), 8.03 (m, 1H), 8.71 (brs, 8H), 9.05-9.12 (m, 3H), 9.42 (m, 1H), 10.10 (brs, 8H), 11.11 (brs, 8H), 11.56 (m, 2H), 11.72 (m, 1H), 12.02 (m, 1H), 12.98 (brs, 8H); LD-MS obsd 2291.4 (M+), 2250.2 (M+-CH3CO), 1181.0 (M+-(Por)Eu), 1111.6 (M+-(Pc)Eu(Pc)), 1067.8 (M+-(Pc)Eu(Pc)-CH3CO); FAB-MS obsd 2284.59, calcd exact mass 2284.58 (C130H90OSN20Eu2); λabs 341, 419, 523, 618, 721 nm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][CH:2]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCCC1=CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2=CCc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
5 g (0.031 mol) of 1H-indene-3-ethanol are dissolved in 50 ml of dry pyridine. The mixture is stirred and cooled using an ice bath, 5.9 g (0.031 mol) of 4-methylbenzenesulphonyl chloride are added in portions, and stirring is continued under cold conditions for 1 h and then at room temperature for 4 h. The solution obtained is poured into a mixture of 100 ml of 10N hydrochloric acid and 200 g of ice. The mixture is extracted twice with diethyl ether, and the organic phase is separated, washed with water, dried over magnesium sulphate and filtered. The filtrate is evaporated under reduced pressure. 7 g of an oily product are obtained which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1[C:27]#[N:28].Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1/[C:27](=[N:30]/[OH:31])/[NH2:28]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(C#N)c(Cl)cnc32)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(/C(N)=N/O)c(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A solution of 5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (Example 138A (160 mg, 0.388 mmol)) in ethanol (4 mL) and water (0.33 mL) was treated with hydroxylamine hydrochloride (54.0 mg, 0.777 mmol) and triethylamine (0.271 mL, 1.942 mmol). The reaction vessel was sealed, and the reaction mixture was heated for 30 minutes at 80° C. Additional hydroxylamine hydrochloride (10.0 mg, 0.143 mmol) added, and the reaction heated for 1 hour at 80° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 50 to 70% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 445.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (step p Example 1) (2.2 g, 5.43 mmol) in DMF (20 ml) was added at 0-5° C. 5-cyano-3-methyl-pyridine-2-carboxylic acid (0.968 g, 5.97 mmol), EDC (1.095 g, 7.05 mmol), HOAt (1.182 g, 8.68 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was added to cold saturated NaHCO3 solution and the product was extracted with TBME. Combined TBME layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain after crystallization from diisopropylether the title compound as colorless crystals: UPLC RtH5=1.472 min); ESIMS: 550; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 10.11 (s, 1H), 8.79 (br s, 1H), 8.01 (s, 1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.21 (dd, 1H), 4.49 (d, 1H), 4.16 (d, 1H), 1.76 (s, 3H), 1.64 (s, 3H), 1.62 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].ClCCl.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:20]([O:15][CH2:14][C@H:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Cl:1])[OH:16])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a solution of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (4E) (0.920 g, 3.89 mmol) in pyridine (5.0 mL)/dichloromethane (15.0 mL) was added pivaloyl chloride (0.574 mL, 4.67 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction was incomplete and additional pivaloyl chloride (0.574 mL, 4.67 mmol) was added. After stirring for 1 h, the reaction mixture was quenched with 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 4F as a colorless oil (1.139 g). LCMS-ESI+ (m/z): [M—O]+ calcd for C18H21ClO2: 304.80. Found: 303.0, 305.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1CC1(NS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), methane-sulfonyl chloride (0.31 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 (2 mL) is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[K+].CS(C)=O>O.[I-].[K+]>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:16]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CCO1
Temperature: 120 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A mixture of 4-benzyl-2-chloromethylmorpholine (22.5 g), potassium cyanide (13 g), potassium iodide (1 g), and dimethyl sulfoxide (40 ml) is heated with stirring at 120° C. for 5 hours. The reaction mixture is cooled, diluted with water, and extracted with diethyl ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to give the title compound (20 g) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2].[OH-].[NH4+:18]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12](=[O:14])(=[O:13])[NH2:18])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(S(=O)(=O)Cl)cc1C
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)Nc1cc(F)c(S(N)(=O)=O)cc1C

Procedure:
The moist 2-acetamido-4-fluoro-5-chlorosulphonyltoluene (3) was heated in 650 ml of concentrated ammonium hydroxide until it reached 50°. The resulting solution was cooled and extracted with ethyl acetate, (10×1000 ml). The extracts were combined and concentrated in vacuo, to give a solid. The latter was purified by dissolving the solid in 350 ml of a 20% aqueous solution of sodium hydroxide, filtering this mixture and acidifying the filtrate with concentrated hydrochloric acid. The precipitate, which separated out, was recovered, then dried; yield: 32.9 g (23.4%); m.p.: 205-207°; literature:1 m.p.: 206-208°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C1C=CC=CN=1)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][O:16][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate (1.0 eq.), imidazole (1.1 eq.), tert-butyldimethylsilylchloride (1.1 eq.) and dimethylaminopyridine (0.1 eq.) in dichloromethane at a concentration of 0.1 M was stirred for 18 hours at which time the volatiles were removed in vacuo. Direct purification of the crude material by column chromatography (20% ethyl acetate/hexanes) yielded cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-((tert-butyldimethylsilyloxy)methyl)piperidine-1-carboxylate. LCMS (m/z): 379.0 (MH-Boc+); LC Rt=5.95 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)Cl>CC#N.C(Cl)Cl>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([Cl:14])[CH:16]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCCC(=O)Nc1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC#N
Product: CCCC(=O)Nc1cccc(NC(=O)c2cccc(Cl)c2)c1

Procedure:
N-(3-Aminophenyl)butyramide (30 mg, 0.168 mmol), 3-chlorobenzoic acid (39.5 mg, 0.252 mmol), HOBt (28.4 mg, 0.185 mmol), and silica-supported DCC (from Silicycle Inc., 362 mg, 0.337 mmol) were added to a 13×100 mm test tube with stir bar. The tube was sealed with a rubber septum and dry DCM (3 mL) was added, then the reaction was stirred for 15 h. 50% CH3CN/DCM (4 mL) was then added, followed by silica-supported trimethylammonium carbonate (from Silicycle Inc., 534 mg, 0.337 mmol). The mixture was stirred for 1 h, then filtered through Celite and washed with 50% CH3CN/DCM (4 mL) and concentrated. The crude solid was redissolved with DCM and purified by column chromatography (EtOAc/hexanes gradient) to yield a white solid after precipitating from hexanes (39 mg, 73%). LRMS (ESI+) (M+H): 317.22.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[C:23](Cl)(Cl)=[S:24]>O1CCCC1>[CH3:10][N:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[C:23]=[S:24])=[CH:17][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N=C=S)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Diisopropylethylamine (344 mg, 2.66 mmol, 2.4 eq.) was added with stirring to a solution of 4-[2-(dimethylamino)ethoxy]aniline (200 mg, 1.11 mmol, 1 eq.) in tetrahydrofuran (2 mL) at 0° C., and then thiophosgene (153 mg, 1.33 mmol, 1.2 eq.) was added dropwise with stirring. The reaction mixture was allowed to warm to room temperature with stirring, and stirred at room temperature for 40 minutes, during which a precipitate formed. The tetrahydrofuran was removed under vacuum, and the residue was dissolved in ethyl acetate and washed with brine (3×10 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4-[2-(dimethylamino)ethoxy]phenyl isothiocyanate (0.20 g) as a dark brown oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([Cl:11])[CH:3]=1.[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:36]([C:37]2[NH:38][CH:39]=[C:40]([CH3:42])[N:41]=2)=[CH:35][N:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46]C2N=CC(C#N)=CC=2)[N:32]=1>>[NH2:12][C:13]1[N:14]=[C:15]([NH:46][CH2:45][CH2:44][NH:43][C:33]2[N:32]=[C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[Cl:11])[C:36]([C:37]3[NH:38][CH:39]=[C:40]([CH3:42])[N:41]=3)=[CH:35][N:34]=2)[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(F)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2-chloro-4-fluorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amine was prepared from 4-fluoro-2-chlorobenzoyl chloride and 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.O>C1COCC1>[O:30]=[C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH:18]=[CH:19][N:14]1[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]=[O:2])[N:6]=[CH:7]2
Reactant: COC(Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CCn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Yield: 233 %

Procedure:
A solution of 1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)-phenyl)pyridin-2(1H)-one (480 mg, 1.08 mmol) in THF (10 mL) was treated with aqueous HCl (9 mL, 2.0 M). The solution was heated to reflux for 1 h, allowed to cool and then treated with H2O (100 mL). The resulting solids were isolated by filtration, washed with H2O and dried under high vacuum for 16 h to give the title compound (1.00 g, 64%) as a light brown solid: ESI MS m/z 398 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C-:20]#[N:21].[Na+]>C(#N)CC.[Cu](I)I>[C:20]([C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:21]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(Br)cnc1Oc1ccc(F)cc1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCC#N
Product: COC(=O)c1cc(C#N)cnc1Oc1ccc(F)cc1
Yield: 71.3 %

Procedure:
A mixture of methyl 5-bromo-2-(4-fluorophenoxy)nicotinate (step 1, 163 mg, 0.50 mmol), sodium cyanide (49 mg, 1.0 mmol), tetrakis(triphenylphohphine) palladium(0) (29 mg, 0.025 mmol), and copper iodide (9.5 mg, 0.05 mmol) in propionitrile (4.0 mL) was heated under reflux for 4.5 h with stirring. The reaction mixture was filtered through a pad of Celite®. The filtrate was partitioned between water (10 mL) and dichloromethane (30 mL). The organic phase was separated, dried (sodium sulfate), and concentrated. The residue was purified by TLC plate developing with hexane/ethyl acetate (3/1) to afford 97 mg (71%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, m), 7.14 (2H, d, J=1.2 Hz), 7.12 (2H, s), 3.99 (3H, s); MS (ESI) m/z 272 (M+).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=O)=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:40])/[CH:37]([CH3:39])[CH3:38]>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:29][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:7][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reactant: CC(C)/C(N)=N/O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(C(C)C)no4)c3)cc12
Yield: 19.5 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)-N′-hydroxyisobutyrimidamide (38 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46-8.54 (1H, m), 8.35 (1H, s), 8.11 (1H, d, J=7.78 Hz), 7.97-8.08 (3H, m), 7.92-7.97 (1H, m), 7.73-7.84 (3H, m), 7.40 (2H, t, J=8.91 Hz), 3.12-3.23 (1H, m), 2.87 (3H, d, J=4.52 Hz), 1.36 (6H, d, J=7.03 Hz). LC-MS retention time: 1.80 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=16.33 min, purity=99%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=13.72 min, purity=99%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[N:14]=[CH:13][CH:12]=1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][CH:12]=[N:11]2)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2nccnc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2nccnc12
Yield: 78.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 1.57 g (10.0 mmol) was reacted with quinoxaline-5-carbaldehyde 1.34 g (8.5 mmol) to obtain the title compound 1.93 g (78%).