Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:28](=[O:30])[CH3:29])[CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1ccc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc21

Procedure:
To a solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (12 g, 36.2 mmol) in THF (300 mL), NaH (1.74 g, 43.5 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) are added. After 1 h the reaction is quenched with aqueous ammonium chloride and extracted with EtOAc. Most of the impurities are removed passing it through a silica gel column eluting with 50:50 heptane:EtOAc to give crude 1-[5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone. This is then dissolved in TFA (300 mL) and heated to 100° C. for 6 hours. At this point the solvent is removed and 1-[5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone isolated via FCC eluting with EtOAc. MS (ESI) m/z 284.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C@H:13]2[CH2:16][C@H:15]([NH2:17])[CH2:14]2)=[CH:7][C:6]=1[F:18])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[N:28]1[CH:29]=[CH:30][N:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[C:32]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:4][C:2]([C:5]1[C:6]([F:18])=[CH:7][C:8]([O:12][C@H:13]2[CH2:14][C@H:15]([NH:17][CH2:37][C:33]3[C:32]4[N:31]([CH:30]=[CH:29][N:28]=4)[CH:36]=[CH:35][CH:34]=3)[CH2:16]2)=[CH:9][C:10]=1[F:11])([CH3:1])[CH3:3]
Reactant: O=Cc1cccn2ccnc12
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](N)C2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](NCc3cccn4ccnc34)C2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of trans-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutanamine (73 mg, 0.286 mmol) in anhydrous DCM (3 mL) was treated with DIPEA (0.06 mL, 0.343 mmol). A solution of imidazo[1,2-a]pyridine-8-carbaldehyde (41.8 mg, 0.286 mmol) in anhydrous DCM (3 mL) was added and the reaction was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (121 mg, 0.572 mmol) was added portionwise and the reaction was stirred at room temperature under nitrogen overnight. Water (10 mL) was added and the phases were separated. The organic layer was concentrated and the residue was purified by MDAP to give the title compound (79.4 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:38][NH2:39])(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:39][NH:38][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:20])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 32 (0.12 mmols, 0.04 g); dodecanoyl hydrazine (0.15 mmols, 0.033 g). Yield: 0.045 g (75%), white solid, m.p.=150° C.-151° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[Br:18])(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[Br:18][C:6]1[CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(O)c(Br)c2)CC1

Procedure:
2-bromo-4-(4-methylpiperazin-1-yl)phenyl acetate 280 mg (1.03 mmol) were dissolved in methanol and reacted with 2 ml of 1 N NaOH. After two hours the reaction was acidified with glacial acetic acid, evaporated and purified on silica with DCM/MeOH 9/1 0.4% 7M NH3 in MeOH. LC/MS (m/z): 273.2 [M+H]+, HPLC (254 nm) method 3 Rt 2.96 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c2nc(Cl)ccc21
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccccn2)c2nc(Cl)ccc21
Temperature: 30 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one were dissolved in 160 ml of hot dimethylformamide and after cooling the solution to 30° C., 4.64 g of a 50% sodium hydride-oil suspension were slowly added thereto. The mixture was stirred at 30° C. for 2 hours and then 80 ml or 129.6 g of 2-bromo-pyridin and 1.2 g of cuprous chloride were added thereto. The mixture was refluxed for 4 hours and was then cooled and evaporated to dryness. The residue was taken up in ammonium hydroxide solution and the mixture was extracted with chloroform. The organic phase was dried and evaporated to dryness and the residue was taken up in petroleum ether. The mixture was filtered and the product was crystallized from 95% ethanol to obtain 6.5 g of 1-methyl-3-(2-pyridyl)-5-chloro-1,3-dihydroimidazo-(4,5-b)-pyridin-2-one in the form of white crystals melting at 192°-194° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][C:8]2=[O:18])=[CH:4][C:3]=1[C:21]([O:23]C)=[O:22].C(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)(O)=O>>[C:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[F:1])[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][C:8]1=[O:18])([OH:23])=[O:22]
Reactant: COC(=O)c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F
Agent: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Product: O=C(O)c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F

Procedure:
The title compound was prepared from 1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione using a procedure similar to those described for the synthesis of compound of Example 2. 1H NMR (DMSO-d6): 13.23 (brs, 1H), 11.75 (s, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.80 (dd, J=6.9 and 2.1 Hz, 1H), 7.67-7.54 (m, 2H), 7.30-7.21 (m, 3H), 5.31 (s, 2H). MS: m/z 315.3 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[C:29]([F:39])[CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[C:29]([F:39])[CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (112 mg, 0.2 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (0.12 mL, 3.93 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC=C(N)C=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: COc1cccc(N)c1
Agent: O=Cc1ccccn1
Product: COc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, m-anisidine (135 mg, 1.1 mmol) and pyridine-2-carboxaldehyde (118 mg, 1.1 mmol) were employed to obtain 2-[2-(3-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+]([O-])=O)[CH:8]=2)[N:3]=1.ClC1C(Cl)=NC2C(=CC=CC=2)N=1.[K][S:29][C:30](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[S:31][K]>>[S:29]1[C:11]2=[N:10][C:9]3[C:4]([N:3]=[C:2]2[S:31][C:30]1=[C:33]([C:36]#[N:37])[C:34]#[N:35])=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: Clc1nc2ccccc2nc1Cl
Product: N#CC(C#N)=C1Sc2nc3ccccc3nc2S1
Yield: 69 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3-dichloroquinoxaline and 3.95 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a light tan powder weighing 2.8 g with a calculated overall yield of 69 percent and has a melting point greater than 320° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].F[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: Sc1ccccc1Cl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
A 2.5 mol/L sodium hydroxide aqueous solution (1.7 mL, 4.4 mmol) and tetrabutylammonium bromide (0.017 g, 0.051 mmol) were added to 2-chlorobenzenethiol (0.17 g, 1.0 mmol), followed by stirring at 25° C. for 10 minutes. To the reaction liquid was added a toluene (1.7 mL) solution of 2-fluoro-5-nitrobenzaldehyde (0.18 g, 1.0 mmol), followed by stirring at 110° C. for 2 hours. After the conventional post-reaction treatment, the residue was purified by silica gel chromatography (eluted by chloroform) to give 2-[(2-chlorophenyl)thio]-5-nitrobenzaldehyde (0.25 g, 83%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[ClH:8].[CH3:9][N:10]1[CH2:15][CH:14]=[C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1>C(O)(=O)C>[ClH:8].[CH3:9][N:10]1[CH2:11][CH2:12][C:13]2[CH:14]([CH:3]3[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]3[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH2:15]1
Reactant: O=C1C=CC(=O)O1
Reactant: CN1CC=C(C=Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCC2=CC(c3ccccc3)C3C(=O)OC(=O)C3C2C1

Procedure:
A solution of 50 g. maleic anhydride and 10 g. 1,2,3,6-tetrahydro-1-methyl-4-styrylpyridine hydrochloride, from example 7, in 100 ml. acetic acid and 100 ml. acetic anhydride previously thoroughly sparged with dry nitrogen is refluxed gently for 3 hours under nitrogen. The reaction mixture is concentrated to 100 ml. volume, and flushed with 300 ml. benzene to remove most of the remaining solvent. The residue is triturated with benzene several times to give 17.5 g. of a crude brown product. This compound is not further purified. It is refrigerated in the dry state for storage.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C:23]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][C:23]([NH2:22])([CH3:28])[CH2:24]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1(N)CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 60.4 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.5 g), 3-amino-3-methylpyrrolidine (0.76 g), DBU (0.77 g), and acetonitrile (30 ml) was refluxed for 7 hours. The precipitated crystals were collected by filtration after cooling, and washed with acetonitrile. The crystals were suspended in water (50 ml) and dissolved by addition of a 10% aqueous solution of acetic acid. The solution was treated with activated carbon, and adjusted to pH 7-8 with 10% aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and then with ethanol, and dried to give 5-amino-7-(3-amino-3-methyl1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid (1.15 g), m.p. 271°-273° C. (decomp.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[NH:19][C:18]4=[O:25])[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39].N12CCCN=C1CCCCC2>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[NH:19][C:18]4=[O:25])[C:11]([NH:51][S:48]([C:45]3[CH:46]=[CH:47][C:42]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1NC(=O)c2cc(OC(C(=O)O)c3ccc4c(c3)OCO4)ccc21
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2ccc3c(c2)C(=O)NC3=O)c2ccc3c(c2)OCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1 g of 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)acetic acid and 0.71 g of carbonyldiimidazole in 100 ml of THF is heated at 60° for 2 hours. 0.93 g of 4-tert-butylbenzenesulfonamide and 0.67 g of 1,8-diaza-bicyclo[5.4.0]-undec-7-ene are then added and the mixture is stirred for a further 1 hour at this temperature. After customary working up, 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxo-isoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide, m.p. 215°, is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:34])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:23]1([CH:22]=[C:21]([F:34])[CH2:20][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[CH2:24][CH2:25]1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(F)cc2F)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(F)cc2F)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 56.8 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.28 g), tetrahydrofuran (2 ml), magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2,4-difluorophenyl)cyclopropane (Example 23) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C8; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2,4-difluorophenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (80 mg, 56%).
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[O:5].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[O:5]=[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
tert-butyl 1-(N-methoxy-N-methylcarbamoyl)ethylcarbamate (39) (2.3 g, 10.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (100 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (30.0 mL, 30.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (60 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat. NaCl (1×50 mL), and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 3.1 g of crude material. The residue was purified by flash column chromatography (15% EtOAc/Hexanes) to give 2.2 g (86%) of 40 as a colorless oil.10 Rf=0.25 (15% EtOAc/Hexanes); IR (film) 3356, 2977, 1680, 1164 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 2H, Ph-H), 7.59 (t, J=7.5 Hz, 1H, Ph-H), 7.48 (t, J=7.5 Hz, 2H, Ph-H), 5.62 (br d, J=6.5 Hz, 1H, carbamate-NH), 5.30 (t, 1H, Boc-NH—CH), 3.78 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.46 (s, 9H, Boc-t-butyl-CH3, 1.40 (d, J=7.0 Hz, 3H, CH—CH3); 13C NMR (125 MHz, CDCl3) δ 199.6, 155.5, 134.3, 133.9, 129.0, 128.8, 80.0, 51.3, 28.6, 20.1; LRMS (ESI-MS m/z): Mass calcd for C14H19NO3 [2M]+, 498.62. Found 499. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:12]([CH3:13])=[C:11]([Cl:14])[N:10]2[N:15]=[CH:16][CH:17]=[C:9]2[N:8]=1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[Cl:6][C:7]1[C:12]([CH3:13])=[C:11]([Cl:14])[N:10]2[N:15]=[CH:16][C:17]([CH:22]=[O:23])=[C:9]2[N:8]=1
Reactant: Cc1c(Cl)nc2ccnn2c1Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)nc2c(C=O)cnn2c1Cl
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
To N,N-dimethyl formamide (9 mL) under nitrogen at room temperature was added POCl3 (3mL) and the resulting slurry was stirred for 5 min. 5,7-Dichloro-6-methylpyrazolo[1,5-a]pyrimidine (5 g) was slowly added and resulting thick mixture was heated at 70° C. for 3 h. The mixture was poured onto ice and basified with sodium hydroxide (5 g). The residue was filtered and the dried precipitate chromatographed on silica gel (eluting with CH2Cl2→20% ethyl acetate/CH2Cl2) to give the title compound (3.74 g); mp 137-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CC(=O)O
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc([C@@H](C)O)ccc1Br
Yield: 71.2 %

Procedure:
A mixture of 1-(4-bromo-3-methylphenyl)ethanone (27.3 g, 128 mmol) and (S)-2-Methyl-CBS-oxazaborolidine (3.6 g, 12.8 mmol) in dichloromethane (500 mL) was added dimethylsulfide-borane (64 mL, 2M in tetrahydrofuran) dropwise at −20° C. and maintained at the same temperature for 2 hours. Acetic acid (15 mL) was added to quench the reaction. The resultant mixture was concentrated to give a residue. Then the mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give (R)-1-(4-bromo-3-methylphenyl)ethanol (19.6 g, 71%)
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]([F:43])([F:42])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:43])([F:26])[F:42])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1csc(-c2ccccc2C(F)(F)F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3C(F)(F)F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid (Intermediate 124) gave 311. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.58 (s, 1H), 7.97-7.93 (m, 1H), 7.89-7.75 (m, 4H), 4.78 (dd, J=10.9, 3.7 Hz, 1H), 4.37-4.19 (m, 1H), 4.14-4.02 (m, 1H), 4.02-3.84 (m, 1H), 3.78 (s, 3H), 3.20-3.08 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.76 (m, 1H), 1.71-1.59 (m, 3H). LCMS (ES+) m/z 484 (M+1).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH:12]1[C:13]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[CH:15]=[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]=1[F:18].[Na]>C1COCC1>[NH2:9][C:10](=[S:11])[N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[C:14]3[C:13]([C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]3[CH:33]3[CH2:34][CH2:35]3)=[CH:12][C:17]=2[F:18])[CH2:24][CH2:23]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
[6R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR279## according to this invention, is made as follows. A solution of benzoyl isothiocyanate (0.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 9) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: Cl.Cl[CH:3]([C:9]1[N:16]2[C:12]([S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[N:11][C:10]=1[C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(S([O-])=O)O.[Na+]>ClCCl>[CH3:8][N:6]([CH3:7])[C:4](=[O:5])[CH2:3][C:9]1[N:16]2[C:12]([S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[N:11][C:10]=1[C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2nc3sc4ccccc4n3c2C(Cl)C(=O)N(C)C)s1
Agent: Cl
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
40 g (0.0938 mole) of α-chloro-N,N-dimethyl-2-(5-methylthien-2-yl)imidazo[2,1-b]benzothiazole-3-acetamide hydrochloride in solution in 1200 ml of dichloromethane are treated with 43.6 (0.283 mole) of Rongalite®, while stirring the mixture at room temperature for 6 h. The suspension is filtered, it is rinsed with dichloromethane and the organic phase is washed (pH=1) with 500 ml of 0.5N sodium hydroxide up to a pH>10, then to neutral pH with a saturated sodium chloride solution. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. A beige-coloured solid is obtained which is purified by chromatography on a silica gel column, eluting with a 95/5 mixture of dichloromethane/methanol. 23.9 g of a white solid are obtained. Melting point: 216°-218° C.