Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Br:18][C:19]1[CH:20]=[C:21]([Br:43])[C:22]2[N:27]=[C:26]([C:28]3[N:29]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:30]=[C:31]([Br:33])[CH:32]=3)[O:25][C:24](=[O:41])[C:23]=2[CH:42]=1>O>[Br:33][C:31]1[CH:32]=[C:28]([C:26]([NH:27][C:22]2[C:21]([Br:43])=[CH:20][C:19]([Br:18])=[CH:42][C:23]=2[C:24]([N:4]([CH3:3])[NH:5][CH3:6])=[O:41])=[O:25])[N:29]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:30]=1
Reactant: CNNC
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNN(C)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a mixture of 0.42 g of N,N′-dimethylhydrazine dihydrochloride, five drops of water, 0.87 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.59 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.52 g of 4-bromo-N-[4,6-dibromo-2-(N,N′-dimethylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH:9]=[C:8]2[C:22]([OH:24])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([N:7]2[C:15]3[C:10](=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH:9]=[C:8]2[C:22]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:22]([C:8]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:15]4[C:10]([CH:9]=3)=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=4)=[O:24])[CH2:27][CH2:26]2)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCNC1
Reactant: COc1cc2c(cc(C(=O)O)n2-c2ccccc2)c(OC)c1OC
Product: COc1cc2c(cc(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4-c4ccccc4)CC3)n2-c2ccccc2)c(OC)c1OC

Procedure:
1-Phenyl-4,5,6-trimethoxyindole-2-carboxylic acid (91 mg) and homopiperazine (14 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[S:8][C:4]=1[CH3:3]
Reactant: Cc1ccc(C(=O)C(=O)O)s1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(C(=O)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 91.4 %

Procedure:
Br2 (0.665 mL, 12.9 mmol) was added dropwise to a solution of (5-methylthiophen-2-yl)-oxo-acetic acid (1.05 g, 6.15 mmol) and sodium acetate (757 mg, 9.23 mmol) in 10 ml of glacial acetic acid and stirred at room temperature for 6.5 hours. The reaction mixture was poured into 150 ml water and extracted with diethyl ether (2×75 ml). The combined diethyl ether layers were extracted with aqueous Na2S2O3, the organic layer was then dried over sodium sulfate, and concentrated under vacuum to provide crude (4-bromo-5-methylthiophen-2-yl)-oxo-acetic acid (1.40 g, 91%). 1H NMR (300 MHz, CDCl3) δ8.35 (1H, s), 2.54 (3H, s).
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26]([N:36]([CH3:37])[CH3:35])=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CNC
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)O)s3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)N(C)C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-methylthiazole-5-carboxylic acid (example 50B, 51 mg, 0.106 mmol), dimethylamine (40% in water, 0.027 mL, 0.213 mmol), HATU (52.6 mg, 0.138 mmol) and 2,6-lutidine (0.025 mL, 0.213 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-8% methanol/dichloromethane). The product was further purified by preparative HPLC. 2-(7-(Dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,4-trimethylthiazole-5-carboxamide (17 mg, 0.032 mmol, 30.0% yield) was obtained as a off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccccc2)c(=O)[nH]c1=O
Yield: 79.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (289 mg, yield: 79.8%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]4[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=4[N:20]=[C:14]3[C@H:13]2[CH:33]([CH3:35])[CH3:34])[N:3]=1.[CH3:36]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH:33]([C@H:13]1[N:12]([C:4]2[N:3]=[C:2]([CH3:36])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=2)[CH2:17][CH2:16][N:15]2[C:18]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=3[N:20]=[C:14]12)([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(Cl)n1)[C@@H]3C(C)C
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C)n1)[C@@H]3C(C)C
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (20 mg, 0.04 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50 mg, 0.4 mmol) in 5 mL of dioxane was added K2CO3 (54 mg, 0.4 mmol) followed by Pd(PPh3)4 (5 mg, 0.004 mmol) under N2 with stirring. The mixture was refluxed for 2 h until the material was disappeared. The reaction mixture was cooled to rt. The dioxane was removed under vacuum. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 1-isopropyl-2-(5-(methoxycarbonyl)-4-methylpyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 75% yield) as a colorless oil. LC-MS MS (ESI) m/z 502.1 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:9][NH2:10]>C1(C)C=CC=CC=1>[CH:1](=[CH:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: CN
Solvent: Cc1ccccc1
Product: NC=Cc1cccnc1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Nicotinaldehyde (10.7 g, 0.1 mol) was dissolved in toluene (100 ml). A 40% aqueous methylamine (23.3 g, 0.3 mol) solution was added. This mixture was subjected to azeotropic dehydration for 3 hours. The product mixture was concentrated under reduced pressure, giving N-nicotinylidenemethylamine (11.7 g, 98% yield)
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I>O>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C[Mg]I
Solvent: O
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrfurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[Si:26]([O:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=12)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[Si:26]([O:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([C:8]3[CH2:9][C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]4[C:7]=3[C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])[S:42][C:41]=12)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCO[Si](C)(C)C(C)(C)C)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO[Si](C)(C)C(C)(C)C)c4s3)C[C@H]12
Yield: 50.5 %

Procedure:
The procedure of Example 1a) was repeated, except that 752 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 1.433 g of 7-(2-t-butyldimethylsilyloxyethyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 703 mg of 4-nitrobenzyl (5R,6S)-2-[7-(2-t-butyldimethylsilyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([OH:27])=[O:24])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(CO)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)O)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
To 2-(3-isopropoxy-5-hydroxymethyl-benzoyl) amino-5-pyridine carboxylic acid (0.33 g, 1.0 mM) in THF (20 ml) under argon, Dess-Martin periodinane (0.46 g, 1.1 mM) was added in one portion. After 45 mins satd. potassium carbonate (20 ml) was added and the THF removed in vacuo. Residue was stirred with 2.0M Na2S2O3 (3.5 ml, 7 mM) for 35 mins then acidified cautiously to pH=1 with 2M HCl. Resulting suspension was filtered, washed with water, diethyl ether, DCM and dried under high-vacuum to give 2-(3-isopropyloxy-5-carboxy-benzoyl) amino-5-pyridine carboxylic acid as a pale yellow solid (0.3 g, 93%); 1H NMR δ (d6-DMSO): 1.32 (d, 6H), 4.82 (m, 1H), 7.58 (m, 1H), 7.84 (m, 1H), 8.11 (s, 1H), 8.29 (s, 2H), 8.87 (s, 1H), 10.02 (s, 1H), 11.34 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Pd](Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCCC
Reactant: Brc1ccccc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1Br

Procedure:
A mixture of 1-bromo-2-iodobenzene (5 g, 17.7 mmol), 1-tridecyne (4.9 ml, 21.2 mmol), triphenylphosphine (5 mg), palladium (II) chloride (5 mg) in triethylamine (45 ml) was refluxed under argon for 15 h. After cooling, the mixture was poured into ice-cold dilute hydrochloric acid and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using hexane. Fractions with Rf of about 0.36 on evaporation gave the title alkyne as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH3:8].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:8][C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[Cl:1]
Reactant: Cc1sc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1cc(Cl)c(CBr)s1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0° C., diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:27][N:26]2[C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn(-c2ccc(OC)cc2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 39.6 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (5.00 g, 16.3 mmol) was combined with 4-methoxyphenylhydrazine hydrochloride (4.00 g, 22.9 mmol) and sodium acetate (4.01 g, 48.9 mmol) in xylenes (30 mL). The reaction mixture was heated to 135° C. for 36 hours using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with water (50 mL) and 1N aqueous hydrochloric acid (50 mL). The organic extract were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 2.14 g of 6-bromo-3-ethyl-1-(4-methoxy-phenyl)-1H-indazole (40% yield). 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3, J=7.7), 3.00 (q, 2, J=7.7), 3.86 (s, 3), 7.03 (d, 2, J=8.9), 7.25 (dd, 1, J=8.5, 1.5), 7.53 (d, 2, J=9.1), 7.58 (d, 1, J=8.5), 7.73 (d, 1, J=1.5). 13C NMR (100 MHz, CDCl3) δ 13.53, 20.34, 55.61, 113.02, 114.70, 121.33, 121.70, 122.45, 123.93, 124.50, 132.90, 140.67, 148.83, 158.42. IR 2970, 2934, 1604, 1519, 1461, 1442, 1300, 1250, 1050, 1035, 945, 832 cm-1. Analysis calculated for C16H15BrN2O: C, 58.02; H, 4.56; N, 8.46. Found: C, 58.39; H, 4.69; N, 8.13.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][O:9]C(=O)C)[NH:5][C:4](=[O:6])[CH2:3]1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1([CH2:7][CH2:8][OH:9])[NH:5][C:4](=[O:6])[CH2:3]1
Reactant: CC(=O)OCCC1(C)CC(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(CCO)CC(=O)N1
Reaction time: 1 h

Procedure:
Under nitrogen at 0°, a solution of 4-methyl-4-(2-acetoxyethyl)-2-azetidinone (0.014 mole) in 25 ml anhydrous methanol is treated with a solution of sodium methoxide (77 mg, 1.4 mmoles) in 5 ml anhydrous methanol. After stirring for 1 hour, the solution is neutralized with glacial acetic acid. Removal of the methanol in vacuo gives crude 4-methyl-4-(2-hydroxyethyl)-2-azetidinone as an oil. The product is purified by chromatography on silica gel eluting with 10% MeOH/CHCl3 to give the alcohol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:8]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:7]2[C:6](=[O:18])[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2cc(CO)ccc2=O)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C=O)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-hydroxymethyl-1-(4-methoxy-benzyl)-1H-pyridin-2-one (35 mg, 151.5 μmol, 1 eq), 4-methyl morpholine N-oxide (26.7 mg, 227.2 μmol, 1.5 eq) and powdered 4 Å molecular sieves in dichloromethane (10 mL) was added in one portion tetrapropylammonium perruthenate (2.7 mg, 7.5 μmol, 0.05 eq). The reaction was stirred at rt for 2 h. After this time, the mixture was filtered through silica and the silica plug was washed with 95:5 dichloromethane/methanol. The filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 2:1 ethyl acetate/hexane to give 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carbaldehyde. Mass Spec. m/z=230 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH3:22])[CH:6]([N:8]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH3:22])[CH:6]([N:8]([C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1N)C1CC1
Yield: 72.5 %

Procedure:
A mixture of 1.02 g (0.003 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (IV-46) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 0.68 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (V-46). This material was used directly in the next step without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[F:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33]>>[F:26][C:27]1[CH:28]=[C:29]([O:34][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1ccc(F)c(F)c1
Product: Fc1ccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3,4-difluorophenol according to the procedure described in Example 74 to afford 2-(3,4-difluorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=463 (M++1); Rt=4.60 min; 1H-NMR 400 MHz (CDCl3): δ 7.05. (m, 3H), 7.19-7.30 (m, 6H), 7.39 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH:1]1([NH:5][CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[OH:8])[CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)=[C:18]=[O:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([OH:8])[CH2:6][N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:18](=[O:19])[NH:17][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:32][CH:33]=1
Reactant: OC(CNC1CCC1)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)C(=O)NCc1ccc(N=C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N(CC(O)c2cccc(Cl)c2Cl)C2CCC2)cc1
Reaction time: 1.5 h

Procedure:
To a test tube containing 0.3 mmol 2-cyclobutylamino-1-(2,3-dichlorophenyl)ethanol in 1 ml CH2Cl2 was added 314 μl of a 0.1 M solution of N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide and 0.43 μl triethylamine. The solution was allowed to stand for 1.5 h, then saturated sodium bicarbonate (1 ml) was added and the resulting mixture extracted with 1 mL EtOAc. The EtOAc extract was washed with water (2×1 ml), and the solvent removed by vacuum centrifugation over 48 h. The resulting solid was dissolved in 450 ml DMF and purified by reverse phase preparatory HPLC (Zorbax 2.5×7 cm C8 column, linear gradient 5-100% CH3CH/H2O (0.1% TFA), 15 mL/Min). The desired fractions were combined and the solvent removed by vacuum centrifugation to give. The desired fractions were combined and placed on a speed vacuum overnight for 15 h to give N-(4-{3-[2-(2,3-Dichloro-phenyl)-2-hydroxy-ethyl]-3-cyclobutyl-ureido}-benzyl)-2,2-dimethyl-propionamide. 1H NMR δH (CD3OD) 7.67-7.66 (d, 1H, J 1.22 Hz), 7.64-7.63 (d, 1H, J 1.23 Hz), 7.38-7.36 (t, 1H, J 7.94 Hz), 7.28-7.25 (d, 2H, J 8.55 Hz), 7.20-7.17 (d, 2H, J 8.24 Hz), 5.33-5.31 (t, 1H, J5.5 Hz), 4.38-4.31 (m, 4H), 3.59-3.57 (d, 2H, J 5.5 Hz), 2.20-1.99 (m, 4H), 1.68-1.56 (m, 3H), 1.20 (s, 9H).