Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([S:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O>C(O)(=O)C.ClCCl.[Zn]>[NH2:1][C:4]1[C:9]([S:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)c1ccc(Sc2cccnc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(Sc2cccnc2N)cc1
Yield: 99.6 %

Procedure:
Added zinc powder (13.88 g, 212.2 mmol) slowly to a solution of methyl 4-(2-nitropyridin-3-ylthio)benzoate (6.16 g, 21.22 mmol) in acetic acid (75 mL) at ambient temperature in an ambient water bath. Stirred for an hour, diluted with dichloromethane, and filtered through celite. Washed the celite pad several times with dichloromethane. Concentrated the filtrate, and partitioned the residue between 2N NaOH and ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to afford the title compound (5.5 g, 99.57% yield).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].[H][H]>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C=CCCCCn2ccnc2)cc1
Reactant: [H][H]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCCCCCn2ccnc2)cc1

Procedure:
Add 1 ml water to 400 mg of the compound prepared in Example 72, then add 100 mg sodium bicarbonate followed by 25 ml ethanol. Add 100 mg PtO and add hydrogen under 30 psi for 20 hr. Partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride then 5% methanol/methylene chloride to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ncc1Cl
Reactant: BrCC1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1cc(OCC2CCC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
To a solution of 2,5-dichloro-4-pyridinol (CAN 847664-65-7, 660 mg, 4.02 mmol) in THF (20 mL) and DMF (20 mL) was added with stirring sodium tert-butoxide (1.16 g, 12.1 mmol) and (bromomethyl)-cyclobutane (CAN 17247-58-4, 2.26 mL, 20.1 mmol). The resulting mixture was stirred at 80° C. for 20 h, cooled and concentrated. The residue was partitioned between water and ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (466 mg, 50%) as white solid. LC-MS (UV peak area, m/z) 97.8%, 232.0293 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])(O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: OC(O)(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1

Procedure:
Oxidation of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanediol according to the oxalyl chloride method of Swern [J. Org. Chem., 44, p 4148, 1979)] gave the titled dione following extractive workup and recyrstallization from hexanes m.p. 85-86.5° C.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH2:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[CH2:29]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](NC=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:30]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH:28][CH:29]=[O:30])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1C[C@@H](N)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C[C@@H](NC=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 92 %

Procedure:
17,17-Bis(ethylendioxy)-7α-formamidoandrostane was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-7α-aminoandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane (II-bc, Prepn. 28). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 8.23 (dd, 1H), 7.97 (d, 1H), 4.00-3.70 (m, 8H), 1.85-1.05 (m, 20H), 0.76 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:15]([O:19][CH2:20]C)(=[O:18])[CH2:16][SH:17].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[S:17][C:16]=1[C:15]([O:19][CH3:20])=[O:18]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1sc2cc([N+](=O)[O-])ccc2c1N
Yield: 46 %

Procedure:
The product from Example 47B (3.73 g, 19.3 mmol) was treated with 1 equivalent ethyl thioglycolate and 1 equivalent K2CO3 in ethanol by the procedure described in Example 41A to yield the title compound (2.35 g, 46%). m.p. 169°-170° C. 1H NMR (300 MHz, DMSO) δ8.90 (d, 1H), 8.37 (d, 1H), 8.20 (dd, 1H), 7.29 (br s, 2H), 4.31 (q, 2H), 1.31 (t, 3H). MS (DCI/NH3) m/e 284 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19])=[N+:12]=[N-:13]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:19])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.45 g, 30.9 mmol) and 4-dimethylaminopyridine (7.55 g, 61.8 mmol) in 100 ml of CH2Cl2 was added the solution of crude 5-azidovaleric chloride in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 1 hr. The solution was washed with 1N aqueous HCl (100 ml), brine (250 ml) and dried over Na2SO4. After evaporation of solvent, 5-(5-azidopentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (8.17 g, 98%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
In a 100 ml. round bottom flask there was placed 2 g. of pivalyl acetonitrile, 0.64 g. of sodium hydroxide, 17.5 ml. of water and 12.5 ml. of ethanol. This mixture was heated to refluxing and a aqueous solution of 1.1 g. of hydroxylamine hydrochloride was added dropwise. When addition was complete the pH of the mixture was about 7.2. This was adjusted to pH about 6.3 using 10% aqueous hydrochloric acid. After 1 hour the pH was about 7.0 and was adjusted with 10% HCl to pH about 6.5. At the end of 2 hours the pH was about 6.8. At the end of 3 hours the pH was about 6.9. At 31/2 hours the pH was about 6.5. The reaction mixture was refluxed overnight and the following morning the pH was about 6.8. The reaction mixture was concentrated using the rotovapor and the solid material which precipitated was filtered off and dried. It weighed 1.3 g., had a melting point of about 103°-104° C., and was determined by vpc to contain 90.68% of 3-amino-5-(t-butyl)-isoxazole and 6.68% of 5-amino-3-(t-butyl)isoxazole. Yield: 65.9% of desired isomer.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11])(=[O:5])=[O:4])[CH3:2].[C:12](Cl)([Cl:14])=[O:13].N1C=CC=CC=1>ClCCl>[CH2:1]([S:3]([N:6]1[CH2:10][CH2:9][N:8]([C:12]([Cl:14])=[O:13])[C:7]1=[O:11])(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCS(=O)(=O)N1CCNC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
The N-ethanesulphonyl-imidazolidin-2-one was then suspended in dichloromethane, a large excess of phosgene was introduced at 0°C, a little pyridine was added and the mixture was left to stand overnight. The excess phosgene was then largely removed by passing in dry air and the product (3-ethanesulphonyl-imidazolidin-2-on-1-carbonyl chloride) was suspended in dichloromethane and filtered off.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:38][CH:37]=[CH:36][CH:35]=4)[NH:1][C:39]3=[O:40])[CH2:16][CH2:15]2)=[CH:29][CH:28]=1
Reactant: Nc1ccccc1C(=O)NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 35.5 %

Procedure:
A mixture of 10.3 parts of 2-amino-N-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-butyl]benzamide, 3.2 parts of 1,1'-carbonylbis[1H-imidazole] and 180 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using first a mixture of trichloromethane and methanol saturated with ammonia (97:3 by volume) and then a mixture of trichloromethane and methanol saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone, yielding 3.8 parts (35.5%) of 3-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 187.3° C. (489).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:17][C@H:15]([C:12]2[N:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=3)=[CH:14][CH:13]=2)[CH3:16])[N:30]=1)[CH3:22]
Reactant: C[C@H](N)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (27 mg, 0.10 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23 mg, 0.10 mmol) and DIPEA (52.4 μl, 0.30 mmol) in DMSO (500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt and RP-HPLC purification (acetonitrile:water) provided the 32 mg of the major product as a white solid. 1H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.23 (dd, J=8.2, 2.4 Hz, 1H), 8.17 (br s, 1H), 8.17-8.12 (m, 1H), 7.98 (dd, J=5.1, 1.7 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.40 (d, J=5.8 Hz, 1H), 5.11 (br s, 1H), 4.69 (br d, J=27.2 Hz, 1H), 4.55-4.12 (m, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.03 (br s, 3H); HRMS (B) m/z 477.1699 (M+H)+.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=1/[CH:5]=[CH:47]/[C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N:32]2[C:33](=[O:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]2=[O:30])[CH:51]=[CH:50][CH:49]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2c(Cl)cccc2Cl)c1

Procedure:
2,6-Dichlorobenzyltriphenylphosphonium bromide was coupled with phthalimide 29. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2,6-dichlorostyryl)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.7041 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.86 (m, 4H), 7.51 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.11 (d, J=16.4 Hz, 1H), 7.01 (d, J=16.8 Hz, 1H), 3.62 (t, J=6.8 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 1.88-1.98 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[I-:25].[Li+]>CN1CCCC1=O>[I:25][C:2]1[CH:3]=[C:4]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: [I-]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)C)c(Br)c2)nc1C
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)C)c(I)c2)nc1C
Temperature: 150 °C
Yield: 71.1 %

Procedure:
120 mg of Ethyl 2-(3-bromo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylate, 100 mg of cuprous iodide and 80 mg of lithium iodide were suspended in 2 ml of N-methyl pyrrolidone, and the suspension was heated at 150° C. for 4 hours with stirring. After completion of the reaction, the product was extracted with ethyl acetate, and the organic layer was concentrated to give a crude crystal. The resulting crystal was purified by silica gel chromatography to give 95 mg of ethyl 2-(3-iodo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylate. The product was hydrolyzed by a conventional process, followed by recrystallization from hexane-ether to give 63 mg of 2-(3-iodo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][CH:15]([F:19])[C:16]([O-])=[O:17]>C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[CH:15]([F:19])[F:14])=[N:3][CH:4]=1
Reactant: O=C([O-])C(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the solution of 2,5-dibromopyridine (16 g, 67 mmol) in toluene (150 mL) was added n-BuLi (27 mL, 67 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 1 hour before the addition of 2,2-difluoroacetate (10 g, 80 mmol). The mixture was stirred at ambient temperature for 16 hours, then diluted with saturated aqueous NH4Cl (80 mL) at 0° C., and extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 5-10% EtOAc/hexane) to afford the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.08 (d, J=6.0 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.05 (t, J=54.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH:15]([CH2:18][CH3:19])[CH:16]=O>>[CH2:18]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])=[N:8][CH:16]=1)[CH3:19]
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Reactant: CCC(Br)C=O
Product: CCc1cnc(-c2ccc(C)cc2[N+](=O)[O-])s1
Yield: 61 %

Procedure:
The procedure described in Example 15-1 was followed, except that 4-methyl-2-nitro-thiobenzamide (56) was used instead of 4-trifluoromethyl-2-nitro-thiobenzamide, and 2-bromo-butyraldehyde (54) was used instead of 1-bromo-3-methyl-butan-2-one, which gave the title compound (60 mg, 61%). LC/MS: (Method I): tR=1.52 min, >95%, m/z (ESI+)=249 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](=O)[CH3:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:9][NH:10][CH:23]([CH3:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC

Procedure:
In accordance with the above preferred reaction scheme 2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone 2 are reacted with sodium cyanoborohydride in methanol, giving 3-chloroalpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 3 which is reacted with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by separation of isomers, giving cyclized derivative 4 which is reacted with boron tribromide in dichloromethane, giving (R*,R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxy phenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 6 which is then reacted first with sodium hydroxide in ethanol and then with hydrogen chloride gas in methanol, giving the product (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl) 2-hydroxyethyl)-amino)propyl-1,3-benzodioxole-2, 2-dicarboxylic acid, dimethyl ester 7.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Nc2ncc(F)c(Nc3ccccc3C(=O)NC(C)C)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(CO)cc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of ethyl 4-({5-fluoro-4-[(2-{[(1methylethyl)amino]carbonyl}phenyl)amino]-2-pyrimidinyl}amino)benzoate (1.47 g, 3.36 mmol) in THF (80 mL) was slowly added a solution of LiAlH4 (1.0M solution, 3.0 eq) at 0° C. After the addition was complete, the reaction mixture was slowly warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with 15 mL of 1.0 M Rochelle's solution. The water phase was extracted by EtOAc (2×30 mL) and the combined organic phases were washed by brine (3×30 mL) then dried over Na2SO4. The solvent was evaporated to produce a solid, which was washed with hexane (3×30 mL), then dried in vacuo to give the desired product. (1.15, 87% yield). MS: M(C21H22FN5O2)=395.44, (M+H)+=396
Reaction SMILES: O[CH:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[C:7]1=O)[C:3](O)=[O:4].[CH3:19][NH:20][NH2:21].B(Br)(Br)Br>CC(O)C>[OH:16][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[C:6](=[CH:2][C:3](=[O:4])[N:20]([CH3:19])[N:21]=3)[CH2:15][CH2:14][C:13]=2[CH:12]=1
Reactant: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Reactant: CNN
Agent: BrB(Br)Br
Solvent: CC(C)O
Product: Cn1nc2c(cc1=O)CCc1cc(O)ccc1-2
Reaction time: 3 h
Yield: 27 %

Procedure:
A solution of the product from step 1 (700 mg, 2.8 mmol) and N-methylhydrazine (0.3 mL) in 2-propanol (10 mL) was heated to reflux 18 h. The solvent was removed under vacuum and the solid was triturated with methanol (2 mL), collected and then suspended in methylene chloride (2 mL) at 0° C. BBr3 (10 mL of 1M solution in DCM, 10 mmol) was slowly added dropwise and the ice bath removed. After 3 h at ambient temperature, saturated NH4Cl solution (10 mL) was added. The DCM was removed under vacuum and the resulting slurry was carefully neutralized with saturated NaHCO3 solution and washed with water. The solids were collected to afford 8-hydroxy-2-methyl-5,6-dihydro-2H-benzo[h]cinnolin-3-one (175 mg, 27%) as a white solid; m p>300° C. MS m/z 229 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
In a Paar flask charged with palladium (10 wt % on carbon, 0.44 g) was added ethyl acetate (30 mL) and 5-nitro-indazole-1-carboxylic acid t-butyl ester (1.61 g, 6.2 mmol). The reaction mixture was hydrogenated at 50 psi for 30 minutes with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of methanol and the combined filtrates were concentrated in vacuo to give a white solid (1.4 g, 100%). 1H NMR (300 MHz, CDCl3), δ: 7.99 (s, 1H), 7.97 (d, J=10, 1H), 6.94 (dd, J=10, J′=2, 1H), 6.92 (d, J=2, 1H), 1.71 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)=[O:30])[CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][N:34]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=3[N:3]=2)[CH:35]=1)=[O:30])[CH3:27]
Reactant: COCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3n2COCCOC)c1
Temperature: 80 °C

Procedure:
A mixture of 2,4,5,6-tetrachloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.275 g, 0.80 mmol), Cs2CO3 (0.524 g, 1.61 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (0.124 g, 0.89 mmol), and DMF (4 mL) was heated to 80° C. for 2 h. The mixture was cooled to 23° C. EtOAc was added and the mixture was washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.166 g, 46%). MS (ESI/CI): mass calcd. for C17H17Cl3N4O4, 446.0; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.01-8.97 (m, 2H), 8.40 (t, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 6.09 (s, 2H), 6.01 (s, 2H), 4.30 (qd, J=7.1 Hz, 2.9, 8H), 3.58-3.51 (m, 2H), 3.44 (d, J=4.9 Hz, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 1.32 (tt, J=7.1 Hz, 1.7 Hz, 6H).