Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[CH2:6]([NH:13][CH2:14][CH2:15][NH2:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH2:15][NH:16][S:1]1(=[O:3])=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCNCc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)NCCN1Cc1ccccc1
Yield: 79 %

Procedure:
To a refluxing solution of sulfamide (27.12 g, 282 mmol) in anhydrous pyridine (250 ml) was added dropwise N-benzylethylenediamine (42.4 ml, 282 mmol) over 3 hours. The resulting solution was refluxed under nitrogen for a further 16 hours before the solvent was removed under vacuum. The residue was dissolved in dichloromethane (100 ml) and washed with 2N hydrochloric acid (1×100 ml). The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic solutions were washed with brine (50 ml), dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane-methanol 95:5) gave 47.3 g (79%) of the title compound as a white solid; δH (360 MHz, CDCl3) 7.32 (5H, m, Ph), 4.34 (1H, br s, --NH--), 4.18 (2H, s, Ar--CH2N--), 3.47 (2H, q, J= 6.4 Hz,--CH2NH--),3.27(2H, t, J=6.4 Hz,--CH2 --); m/z (CI) 213 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([C:18](=O)[CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH2:18][CH2:19][CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:1]
Reactant: O=C(CC1CCNCC1)c1cc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cl
Product: Clc1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1

Procedure:
The operation is as in Example 14, but starting from 6 g of 1-[2-(4-chloro-phenyl)-4-quinolyl]-2-(4-piperidyl)ethanone, prepared as indicated in Example 7, 2.5 g of 98% hydrazine hydrate and 2.73 g of potassium hydroxide in 25 ml of diethylene glycol. 2.1 g are obtained of 2-(4-chloro-phenyl)-4-[2-(4-piperidyl)-ethyl]-quinoline in the form of monohydrochloride, which melts above 260° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C.CCOC(C)=O>[C:34]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])(=[O:36])[CH3:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 88.7 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol) and acetic anhydride (2.42 mL, 25.6 mmol) in acetic acid (5 mL) was stirred at 130° C. for 3 days. Cooled to rt, diluted with EtOAc, extracted with sat. NaHCO3-sol., dried over Na2SO4, filtered off and evaporated totally to give a crude product, which was purified by silica gel column chromatography with n-heptane/ethyl acetate followed by trituration with diethyl ether/n-heptane to give the title compound (290 mg, 88%) as a white solid. MS (ISP) 512.0 [(M+H)+]; mp 244° C.
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:32])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]=1[C:28]([O:30]C)=O.Cl.[NH2:34][CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37].O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[C:16]=1[C:28](=[O:30])[N:34]([CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37])[C:14]2=[O:32])[CH3:27]
Reactant: NC1CCC(=O)NC1=O
Reactant: CCOC(=O)NCc1cccc(C(=O)OC)c1C(=O)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Yield: 46.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5 mmol) was added to a stirred suspension of methyl-3-[(ethoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (1.54 g, 5 mmol) and aminoglutarimide hydrochloride (0.86 g, 5 mmol) in DMF (15 ml). The mixture was heated to 120° C. for 24 hours. The mixture was cooled to room temperature and poured into water (150 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the ethyl acetate solution was washed with water (30 ml), brine (30 ml) and dried. Solvent was removed and the residue was purified by flash chromatography (dichloromethane/ethyl acetate 7 to 3) to give 0.84 g (45%) of the product as a white solid: mp 187-189° C.; 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 7.76-7.58 (m, 4H), 5.06-4.99 (dd, J=5.4 and 12.6 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.91 (q, J=7.0 Hz, 2H), 2.79-2.70 (m, 1H), 2.51-2.38 (m, 2H), 1.96-1.86 (m, 1H), 1.06 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 172.89, 169.93, 167.55, 167.05, 156.72, 139.69, 134.91, 132.90, 131.58, 127.04, 121.97, 60.15, 48.90, 39.34, 30.98, 22.04, 14.69; Anal. Calcd. For C17H11N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.94; H, 4.81; N, 11.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].C(O)(=O)[CH:15]([CH2:17][C:18](O)=O)[OH:16]>[Cl-].[Na+].O>[S:9](=[O:11])(=[O:10])([OH:13])[OH:12].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:15]([OH:16])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2ccc(O)nc2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2,6-Diaminopyridine (167 g, 1.53 mol) was added in portions to sulfuric acid (1.14 kg, 11.7 mol) at 40° C. The temperature of the solution was maintained at 40-50° C. during the addition with a water bath. When all of the 2,6-diaminopyridine was dissolved, the solution was cooled to 20° C. Malic acid (206 g, 1.53 mol) was added to the solution and the reaction mixture was gradually heated to 110° C. over 90 minutes. The mixture was stirred at 110-120° C. for one hour, cooled to room temperature, and poured slowly into a cold brine solution (167 g NaCl, 1.6 kg ice water). The quenched mixture was stirred at room temperature for one hour and filtered. The material was washed with hexanes (335 mL) and dried at 60° C. under vacuum to yield 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt as a yellow solid: 354 g, 89% yield; MS (DCl) M+1 at 162, 100%; 1H NMR (200 MHz, DMSO-d6) δ 4.32 (br. s, 5H, —OH, —NH2, H2SO4), 6.41 (d, J=9.0 Hz, 1H, C6), 6.56 (d J=9.0 Hz, 1H, C5), 7.85 (d J=6.6 Hz, 1H, C3), 7.91 (d J=6.6 Hz, 1H, C4).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)([CH3:3])[CH3:2].[I:14]Cl>CO>[I:14][C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[CH3:11]
Reactant: CSc1nc(C)cc(NC(C)C)n1
Reactant: ClI
Solvent: CO
Product: CSc1nc(C)c(I)c(NC(C)C)n1
Reaction time: 3 h

Procedure:
To a crude solution of N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol), prepared using analogous procedures as described in Example 1, in 400 mL of methanol was added ICl (40.0 g, 246 mmol) in small portions at room temperature. The reaction mixture was then stirred at for 3 h monitoring by LC/MS. After evaporation of solvent by rotary evaporator, the residue was triturated with acetone to yield 5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H), 1.41 (d, J=6.4, 6H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: CC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title ketone of Example 3 (1.0 g, 0.0032 mole) was dissolved in 10 ml of absolute ethanol and the solution cooled to about 0° C. in an ice bath and 31 mg of sodium borohydride was added. The reaction was stirred for about one hour and acetone was added. The solvents were removed in vacuo, the residue extracted twice with benzene, the organic extracts combined and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product which was chromatographed on silica to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[CH2:25]([NH:29][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC(C)CN
Product: CC(C)CNCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and isobutylamine to give a yellow solid. MS m/z: 391.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=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.[Cu]I>[CH3:9][Si:10]([C:13]#[C:14][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)C#Cc1cccnc1N
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
To a solution of 2-amino-3-bromopyridine (5.72 g, 33.1 mmol) in N-methylpyrrolidinone (120 mL) were added trimethylsilyl acetylene (9.36 mL, 66.2 mmol), tetrakis(triphenylphosphine)palladium (0) (1.91 g, 1.66 mmol), copper (I) iodide (630 mg, 3.31 mmol) and N,N-diisopropylethylamine (11.5 mL, 66.2 mmol) at room temperature, which was stirred under nitrogen atmosphere for 6 hours at 70° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (5.94 g, 94%).
Reaction SMILES: ClC1C=[C:4](C=CC=1)[C:5]([O:7]O)=O.[Cl:12][CH2:13][CH2:14][N:15](CCCl)[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:40])([CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:18]([CH3:41])[CH:17]=1.[Cl:45]CCl>>[C:36]([O:35][C:33]([NH:32][CH2:31][C:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]([O:7][CH2:5][CH2:4][Cl:45])[CH2:14][CH2:13][Cl:12])=[CH:17][C:18]=1[CH3:41])([CH3:40])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:34])([CH3:37])([CH3:39])[CH3:38]
Reactant: ClCCl
Reactant: Cc1cc(N(CCCl)CCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cc(N(CCCl)OCCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; U.S. Pat. No. 5,602,278; Kirkpatrick, et al., Anti-Cancer Drugs, 1994, 5, 467-472; and U.S. Pat. No. 7,399,785), tert-butyl 4-(tert-butoxycarbonylamino)-3-[4-(2-chloroethoxy(2-chloroethyl)amino)-2-methyl-phenyl]-3-methyl-butanoate (24a) is prepared by adding 3-chloroperoxybenzoic acid (1.42 g, 80 wt-%, 6.6 mmol) to a solution of tert-butyl 3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)-3-methyl-butanoate (7o) (2.52 g, 5.0 mmol) in dichloromethane (DCM) (30 mL) at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS till completion. After quenching with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO3), the reaction mixture is extracted with DCM (3×). Further aqueous work-up and purification by silica gel column chromatography yield the title compound (24a).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30]CC)=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCC)CCC>>[ClH:1].[C:10]1([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: ClCCCCOCCN(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: Cl
Product: O=C(O)[C@@H]1CCCN(CCCCOCCN(c2ccccc2)c2ccccc2)C1
Temperature: 150 °C

Procedure:
A mixture of 1-chloro-4-(2-(diphenylamino)ethoxy)butane (2.0 g, 6.6 mmol), ethyl (R)-3-piperidinecarboxylate (1.1 g, 7.0 mmol), potassium carbonate (1.0 g, 7.2 mmol) and dry dibutylether was heated at 150° C. for 4 h. The mixture was cooled, filtered and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (150 g) using a mixture of n-heptane and THF (4:1) as eluent. This afforded 1.5 g (34% calculated from 2-(diphenylamino)ethanol) of
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[O:7]1)=[O:5])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([OH:7])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1OC1c1cccc2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(O)Cc1cccc2ccccc12

Procedure:
To an ethanol (400 mL) solution of 3-naphthalen-1-yl-oxirane-2-carboxylic acid ethyl ester (21.26 g, 87.8 mmol) was added 5% palladium hydroxide on carbon (1.0 g). The reaction was then pressurized to 50 psi with hydrogen for 2 h. The reaction was then filtered through a celite pad. The cake was washed with ethanol (100 mL). The reaction was then concentrated under reduced pressure to yield 2-hydroxy-3-naphthalen-1-yl-propionic acid ethyl ester as an oil. 1H NMR(300 MHz, DMSO) 8.05 (d, 1H), 7.89(d, 1H), 7.79(d, 1H), 7.34 (m, 4H), 5.58 (d, 1H), 4.32 (dd, 1H), 4.04 (q, 2H), 3.44 (dd, 1H), 3.24 (dd, 1H), 1.05 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:15]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[N:7]=[C:2]([C:34]3[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=3)[N:3]=2)[CH:20]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
(S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) (350 mg, 0.91 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (239 mg, 1.09 mmol), Pd(PPh3)2Cl2.DCM (37 mg, 0.05 mmol) and Na2CO3 (145 mg, 1.36 mmol) were dissolved in a mixture of DME:H2O (4:1) and stirred at 120° C. under microwave for 30 mins. The reaction mixture was partitioned between H2O and DCM. The organic layer was recovered, dried over MgSO4, filtered and the solvent removed in vacuo to yield the title compound as a brown solid (128 mg, 0.29 mmol, 32% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
The product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.20 mL, 0.40 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was suspended in tetrahydrofuran (10 mL) and adsorbed onto approximately 5 g of silica gel and evaporated. The product was eluted with methanol in chloroform. Product containing fractions were combined and evaporated under vacuum to give the title compound (0.032 g, 42%). MS (ESI−) m/z 417 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01 (d, J=6.62 Hz, 6 H) 1.88 (m, 1 H) 2.83 (s, 2 H) 6.60 (s, 1 H) 7.41 (d, J=4.04 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.65 (d, J=8.46 Hz, 1 H) 7.77 (t, J=7.91 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.35 (d, J=4.78 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[N:21](OC(C)(C)C)=[O:22].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21][OH:22])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)ON=O
Reactant: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-fluoropyridin-4-yl)-1-(3-trifluoromethyl-phenyl)ethanone (3) (10.80 g, 0.038 mol) in ethanol (200 mL), at −10° C., under argon, was added tert-butyl nitrite (5.0 mL, 0.042 mol) and hydrochloric acid (12.2 mL, 2.5M in ethanol, 0.031 mol) dropwise while maintaining the temperature below −5° C. Upon completion of additions, the reaction was allowed to warm to RT for 2 hrs. The reaction mixture was then concentrated in vacuo , diluted with water (100 mL), basified with saturated sodium bicarbonate (200 ml), and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (300 mL), dried with brine (300 mL) and anhydrous sodium sulfate, filtered and concentrated to an oil which weighed 11.4 g (95%). 1H NMR (300 MHz, CDCl3) d 8.31 (s, 1 H, Ar), 8.29 (d, J =5.3 Hz, 1 H, Pyr), 8.24 (d, J=7.8Hz, 1 H, Ar), 7.92 (d, J=8.1 Hz, 1 H, Ar), 7.71 (t, J=7.8 Hz, 1 H, Ar), 7.40 (d, J=5.1 Hz, 1 H, Pyr), 7.23 (s, 1 H, Pyr).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=CC=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@H]2[C@H](O)C[N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])C2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[C@H:12]([OH:20])[CH2:13][N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:19]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting benzyl(trans)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.38, 5.17, 4.48, 4.38, 4.28, 4.12, 3.91; 3.42, 2.86–2.78, 2.58, 1.32–1.24; HRMS (FAB) calcd for C20H25BrN4O3+H 449.1189, found 449.1175.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].[C:25](=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][C:36](=O)CCl)(=[O:33])[CH3:32]>CC(C)=O>[C:31]([O:34][C:35]1[CH2:36][S:2][C:1]([CH3:25])=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCc1ccc(OC)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(OC(C)=O)CSC(C)=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105.4 %

Procedure:
To a stirring solution of p-methoxybenzyl α-thioformamido-diethylphosphonoacetate (114 mg., 0.3 mmole) in acetone (1.5 ml) is added powdered potassium carbonate (124 mg, 0.9 mmole). The resulting mixture is stirred for 5 minutes at room temperature and under a nitrogen atmosphere, then treated with a solution of 1-acetoxy-3-chloro-2-propanone (48 mg, 0.32 mmole) in acetone (0.5 ml). After having been sitrred for 3 hours at room temperature, the mixture is filtered to remove the salts which are washed with acetone. The combined filtrate and washings are evaporated in vacuo to a dark oil. The residue is dissolved in CCl4 (6 ml), washed with aqueous phosphate (1 ml of 1M dipotassium phosphate + 2 ml water) and water (2 × 3 ml)., dried over magnesium sulfate, and evaporated in vacuo to give crude p-methoxybenzyl 5-acetoxy-methyl-6H-1,3-thiazine-4-carboxylate (106 mg) as an orange oil.