Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:4]=1[OH:11])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(C)=O>C(#N)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCc1cc(CO)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CO)cc1CC
Reaction time: 18 h
Yield: 61.6 %

Procedure:
To a solution of 2-ethyl-4-(hydroxymethyl)phenol (3.67 g, 24.1 mmol) in anhydrous acetonitrile (125 mL) was added caesium carbonate (8.65 g, 26.6 mmol), the reaction mixture was then flushed with nitrogen and cooled to 0° C. before addition of ethyl bromoacetate (2.68 mL, 24.1 mmol). The reaction mixture was allowed to gradually attain room temperature and stirred for 18 h. Further ethylbromoacetate (0.26 mL, 2.4 mmol) was added and stirring continued for 4 h. The reaction mixture was diluted with water (100 mL) and then extracted EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4) filtered and evaporated. Purification by Biotage™ chromatography (Silica, 90 g) eluting 4:1 cyclohexane:EtOAc, then EtOAc afforded the title compound as a pale yellow gum (3.54 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:15]>>[CH2:14]([N:16]([C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:13])[C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:15]
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NCC)CC2
Product: CCN(C(=O)C1(c2ccc(F)cc2)CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopropanecarboxylic acid and propyl [(7R)-7-(ethylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 435.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL) was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL of dichloroethane and then heated to 60° C. for 30 min. Another flask containing a suspension of 8.02 mL (81.8 mmol) of 1,3-difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethane was prepared, to this was added the previously prepared acid chloride suspension in portions. The resulting suspension was refluxed for 4 h, cooled and then poured over ice and HCl. The acidic solution was extracted with CH2Cl2 (3×300 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized from hexanes to afford 9.5 g (61%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C14H15F2NO2, 267.11; m/z found, 268.1 [M+H]+, 1H NMR (CDCl3, 400 MHz): 7.87 (dt, J=8.41, 6.65 Hz 1H), 6.98 (m, 1H), 6.88 (ddd, J=10.96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32 (dtt, J=10.76, 3.91, 1.37 Hz, 1H), 3.19 (ddd, J=13.89, 11.93, 2.93 Hz, 1H), 2.79 (ddd, J=13.89, 12.24, 2.93 Hz, 1H), 2.10 (s, 3H), 1.95 (br d, J=12.91 Hz, 2H), 1.72 (br m, 1H), 1.56 (br m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1)=O.Cl.[NH2:29][OH:30].[OH-].[Na+]>C(O)C.O>[CH:1](=[N:29][OH:30])[C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reaction time: 0.5 h

Procedure:
To a suspension of 6.6 g (0.02 mole) of 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (Example 69) and 2.0 g (0.03 mole) of hydroxylamine hydrochloride in 25 ml of ethanol was added dropwise a solution of 1.6 g (.04 mole) of sodium hydroxide in 5 ml of water. The reaction mixture was stirred for 30 minutes and heated under reflux for 5 minutes. A yellow solid precipitated. The reaction mixture was diluted with water, extracted with methylene chloride, and the extract was dried over potassium carbonate and concentrated. The resulting oil was dissolved in ether and filtered. Evaporation of the ether gave the product, 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole oxime, as an oil which was crystallized by the addition of pet. ether. The oxime was dissolved in ether and the solution was acidified to give 3.8 g of the hydrochloride salt; mp. 200° -205° (with dec. starting at 185°).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([N:21]([CH3:22])[CH3:20])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Reactant: CNC
Product: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
b 2) A mixture of 1.84 g of 1-acetyl-4-(4-fluorobenzoylmethyl)piperidine and 6 ml of a 50% aqueous solution of dimethylamine was stirred at room temperature for 3 days and the reaction mixture was worked up as in Example 1 to give 1.8 g of colorless crystals melting at 136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][C:2]1([CH3:1])[C:3]([CH3:17])([CH3:16])[O:4][B:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:43]3[CH2:47][CH2:46][CH2:45][C@H:44]3[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:13])=[CH:14][CH:15]=2)[O:6]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.00 g, 8.06 mmol) in DMF (20 mL) was added HATU (6.20 g, 16.3 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (2.00 g, 11.7 mmol) and DIPEA (4.20 g, 32.5 mmol). The reaction mixture was stirred at rt overnight, and was quenched with H2O (20 mL). The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:20-1:10 v/v) to obtain compound 17a as a yellow solid (1.40 g, 37% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H32BNO5: 402.2 (M+H). Found 402.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([F:36])([F:35])[F:24])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccccc2C(F)(F)F)cc1
Yield: 49.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.057 g; 0.164 mmol), 2-(trifluoromethyl)phenylboronic acid (0.031 g; 0.164 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.0082 mmol), sodium carbonate (0.035 g; 0.328 mmol), sodium iodide (0.049 g; 0.328 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.037 g (49%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:37])[C@@H:4]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23](=[O:36])[N:5]2[C:6]=1[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>[Zn].C(O)(=O)C>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[N:5]2[C:23](=[O:36])[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:4]2[C:3]1=[O:37]
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1C(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
The pivaloyloxymethyl 2-methyl-6-(5-methyl-3-phenylisoxazole-4-carboxamido)-1-oxocarbapen-2-em-3-carboxylate of Example 35 was reduced with zinc (2.22 g.) in 5.3 ml. of acetic acid-30% tetrahydrofuran, by methods detailed in Example 2, and isolated according to methods detailed in Examples 2 and 32, affording pivaloyloxymethyl 2-methyl-6-(5-methyl-3-phenylisoxazole-4-carboxamido)-1-oxocarbapenam-3-carboxylate [100 mg., 50% over-all; ir (CH2Cl2) 1790, 1750, 1670 cm-1 ].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([NH2:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:12]([NH:14][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:13]
Reactant: CCN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCNC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (2 g, 12.8 mmol), and ethylamine (6.4 mL, 12.8 mmol), and sodium triacetoxyborohydride (8 g, 38 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1c(N)c(=O)c1=O
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Solvent: CCO
Product: Nc1c(NCCCOc2cc(CN3CCCCC3)ccn2)c(=O)c1=O
Yield: 64.9 %

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione (0.5 g) and 3-[4-(piperidinomethyl)pyrid-2-yloxy]prop-1-ylamine (1.05 g) were refluxed in ethanol (25 ml) for 4 hours. A solid formed during the reaction. The reaction mixture was cooled and the solid collected by filtration. Recrystallisation of the solid from ethanol/methanol afforded the title product (0.88 g), m.p. 226°-8° C.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Temperature: 120 °C
Yield: 123.2 %

Procedure:
A mixture of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide (1.68 g, 4.54 mmol), Pd(OAc)2 (20 mg, 0.091 mmol), tri-o-tolylphosphine (55 mg, 0.18 mmol), triethylamine (1.25 mL), acetonitrile (2.5 mL) and methyl acrylate (0.83 mL, 9.08 mmol) were placed in a stainless steel bomb and heated to about 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the solid reaction mixture was collected, washed with ether and dried to afford 2.1 g of crude product which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:34][CH2:33][NH:32][CH2:31][C:28]21[CH2:30][CH2:29]2>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:31][C:28]5([CH2:30][CH2:29]5)[N:27]([CH3:26])[CH2:34][CH2:33]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN1CCNCC12CC2
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)C5(CC5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-1.34 (m, 4 H) 2.33 (d, J=2.27 Hz, 3 H) 2.91 (s, 3 H) 3.31-3.85 (m, 6 H) 7.62 (d, J=7.83 Hz, 1 H) 7.70-7.78 (m, 1 H) 7.82-8.75 (m, 4 H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCc2cc(Oc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In an oven-dried round-bottomed flask was combined 5-hydroxy-1-indanone (112 mg, 0.76 mmol), phenylboronic acid (170 mg, 1.51 mmol) and anhydrous copper (II) acetate (195 mg, 1.13 mmol) in 2.5 mL of dichloromethane. Anhydrous pyridine (0.11 mL, 1.5 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated to dryness and was purified with ISCO column chromatography (Teledyne Isco Inc., Lincoln Nebr.) (0-40% ethyl acetate/heptanes gradient) to give the desired product (SM-1i, 170 mg, 97%) as a clear oil which solidified on standing. MS (ES+) 225.3 (M+H)+. 1H NMR (CDCl3) δ 2.48-2.70 (m, 2H), 2.87-3.08 (m, 2H), 6.78-7.01 (m, 2H), 7.03-7.11 (m, 2H), 7.15-7.30 (m, 1H), 7.32-7.53 (m, 2H), 7.70 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25][OH:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][OH:26])[CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(CO)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 70.7 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (30-03) (2 g, 69.57%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (29-03) (3.5 g, 5.4 mmol) as an off-white solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[O:17]1CC[CH2:19][CH2:18]1>C(OC(=O)C)(=O)C>[C:18]([N:10]1[C:9](=[O:14])[CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[O:12][C:11]1=[O:13])(=[O:17])[CH3:19]
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(C)=O)C1=O
Reaction time: 16 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (100 mg.) was dissolved in 2.5 ml. of tetrahydrofuran. Excess acetic anhydride (4 drops) was added, and the mixture allowed to stand at room temperature for 16 hours. Evaporation to dryness gave 3-acetyl-5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione [Rf 0.75 (1:1 ethyl acetate: chloroform; m.p. 160°-162° C⟧
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2([CH3:37])[NH:35][C:34](=O)[CH2:33][O:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>COCCOC>[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2([CH3:37])[NH:35][C:34](=[S:10])[CH2:33][O:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(N)c2)COCC(=O)N1
Solvent: COCCOC
Product: CC1(c2cccc(N)c2)COCC(=S)N1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Lawesson's reagent (0.69 g, 1.64 mmol, 1.3 eq.) was added in one portion to a suspension of 5-(3-amino-phenyl)-5-methyl-morpholin-3-one (0.26 g, 1.26 mmol) in 1,2-dimethoxyethane (10 ml); the reaction mixture was stirred at 80° C. for 18 hours. After complete conversion, the solvent was partially removed at reduced pressure and the dark orange oil diluted with dichloromethane (5 ml) before washing with 1 M HCl (2×5 ml). The aqueous phase was brought to pH 8 and extracted with dichloromethane (4×10 ml) to yield the (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione as a yellow oil (0.16 g, 57% of theory). Mass (calculated) C11H14N2OS [222.31]; (found) [M+H]+=223.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N([O-])=O.[Na+].[I-:16].[K+].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O.O.[Cu]>[I:16][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(N)ccc1O
Reactant: [I-]
Agent: [Cu]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: CC(=O)c1cc(I)ccc1O
Temperature: 65 °C
Reaction time: 0.58 h
Yield: 11.1 %

Procedure:
To a stirring solution of 1-(5-amino-2-hydroxy-phenyl)-ethanone (6.856 g,46 mmol) in 98% sulfuric acid (24 ml) and water (19 ml) was added sodium nitrite (3.30 g, 48 mmol, 1.05 equ) in water (5.5 ml). The reaction was stirred for 35 minutes, then sulfuric acid (4 ml), copper powder (0.17 g, 0.3 mmol, 0.06 equ) and potassium iodide (8.80 g, 53 mmol, 1.16 equ) in water (5.5 ml) added. The mixture was then heated slowly to 65° C. and maintained at 65° C. for 2 hours. The reaction was then cooled, water (25 ml) and sodium hydrogen carbonate added. More water was added, then extracted into a mixture of ethyl acetate and dichloromethane, then ethyl acetate (2×). The combined organic layers were washed with brine then concentrated in vacuo. This mixture was then taken up in ethyl acetate and 2 M HCl, filtered and the organic layer dried (MgSO4) and concentrated in vacuo to give 1-(5-iodo-2-hydroxy-phenyl)-ethanone 52 (1.339 g, 39%) as a purple oil. This was then used in the next reaction.
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=1.[CH3:25][S:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>C(O)CCC.C(OCC)(=O)C>[F:24][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])=[N:14][C:9]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][S:26][CH3:25])[CH:29]=2)=[N:10][CH:11]=1
Reactant: CSCc1cccc(N)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1nc(Nc2cccc(CSC)c2)ncc1F
Temperature: 140 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.61 mL; 2.45 mmol) was added to a stirred solution of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (630 mg; 2.45 mmol) and 3-[(methyl-sulfanyl)methyl]aniline (564 mg; 3.68 mmol) in 1-butanol (5.4 mL). The batch was stirred at 140° C. for 16 hours. After cooling the batch was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 2:1) to give the desired product (662 mg; 1.77 mmol).