Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:7][N:8]([C@H:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH:9](C1C=CC=C(Cl)C=1)[C:10]([OH:12])=O.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:7][N:8]([C@H:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH2:9][CH:10]([C:4]1[CH:5]=[CH:6][CH:33]=[C:34]([Cl:1])[CH:35]=1)[OH:12]
Reactant: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)C(C(=O)O)c2cccc(Cl)c2)cc1OC
Reactant: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)CC(O)c2cccc(Cl)c2)cc1OC

Procedure:
A solution of 5 g. of (R)-N-(3,4-dimethoxybenzyl)-N-(3-chlorophenylcarboxymethyl)-1-(3,4-dimethoxyphenyl)-prop-2-ylamine hydrochloride in 100 mL of methanol at -78° C. is treated with 0.71 g. of sodium borohydride, added in several portions over one hour. The mixture is stirred for an additional hour and then allowed to reach room temperature. The solvent is removed by evaporation to yield (R)-N-(3,4-dimethoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine, which is dissolved in methylene chloride, washed with 3N aqueous sodium hydroxide and brine, and dried over magnesium sulfate. 1H NMR (250 MHz, CDCl3) d 1.02 (d, 3H, J=6.3 Hz), 2.4-2.7 (m, 4H), 3.1-3.25 (m, 1H), 3.35 (1/2ABq, 1H, J=13.3 Hz), 3.69 (s, 3H), 3.75 (s, 3H), 3.81 (br. s, 6H), 3.7-3.8 (m, 1H), 4.21 (m, minor isomer CHOH), 4.55 (m, major isomer CHOH), 6.52-6.76 (m, 6H), 7.19-7.33 (m, 4H). The product contains 97.9% R,R diastereoisomer and 2.1% S,R diastereoisomer.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH3:41])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1>>[CH3:41][N:13]([CH3:12])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[C:32]([C:2]#[C:1][C:3]4[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=4)[CH:33]=3)=[O:36])=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1
Reactant: C#Cc1cnc(C(N)=O)n1C
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1C#Cc1cnc(C(N)=O)n1C

Procedure:
The title compound can be synthesized from 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide and (R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 2. 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide is prepared as in Example 2.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]([F:18])([F:31])[F:30])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: OB(O)c1ccccc1OC(F)(F)F
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+]
Product: Cc1nc(-c2ccccc2OC(F)(F)F)n2c1c(C)nc1ccc(F)cc12
Yield: 85.3 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (80 mg, 85% yield). EIMS 376.0 [M+H]+.
Reaction SMILES: [Na].[NH2:2][N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CO>C(O)C>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:21]=[CH:22][C:23]([C:24]2[N:25]=[C:4]3[C:5]4[C:10]([CH:11]=[CH:12][N:3]3[N:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:26][CH:27]=1
Reactant: Nn1ccc2ccccc2c1=O
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CCO
Solvent: OCCO
Product: c1ccc(-c2ccc(-c3nc4c5ccccc5ccn4n3)cc2)cc1
Temperature: 25 °C

Procedure:
A solution prepared from 0.075 g. of sodium dissolved in 20 ml of absolute ethanol was added to a suspension of 0.640 g. (0.004 mole) of 2-amino-isoquinoline-1(2H)-one and 0.720 g. (0.004 mole) of 4-phenyl-benzonitrile in 20 ml of absolute ethanol. The resulting mixture was refluxed for 30 minutes on an oil bath, then 15 ml. of ethylene glycol were added and the ethanol was distilled off by adjusting the temperature of the oil bath at about 150° C. After three hours the reaction mixture was cooled to room temperature whereby the title compound crystallized out. It was recovered by filtration and re-crystallized from a mixture of methylene chloride/diethyl ether=1/1. Yield 650 mg. M.p. 203°-5° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH2:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.345 g, 1.39 mmol) was treated with Trifluoroacetic Acid (0.418 mL, 5.42 mmol) in Methylene chloride (3.00 mL). Partial conversion after 3 h, added additional 1 ml TFA and allowed to stir at rt for 16 h. Complete conversion to more polar peak on LCMS. Reaction mixture was concentrated to an orange film which was used without purification in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][C:71](=[O:89])[NH:72]/[C:73](/[NH:85][CH2:86][CH:87]=[CH2:88])=[N:74]\[C:75](=[O:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:77]([O:76][C:75]([NH:74][C:73]([NH:85][CH2:86]/[CH:87]=[CH:88]/[C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([CH3:54])=[CH:42][C:41]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:45]=2)=[CH:48][CH:49]=1)=[N:72][C:71]([O:70][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:89])=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Reactant: C=CCN/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Yield: 45.4 %

Procedure:
To an acetonitrile solution (3 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (271 mg, 0.305 mmol) were added dibenzyl[(Z)-(allylamino)methylylidene]biscarbamate (335 mg, 0.914 mmol), palladium(II) acetate (18 mg, 0.0791 mmol), tri-O-tolylphosphine (61 mg, 0.201 mmol) and triethylamine (154 mg, 1.52 mmol), and reacted at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (163 mg, 46%) as a pale yellow amorphous compound.
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]([OH:16])(=[O:15])[C:12]#[C:13][CH3:14]>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1]/[C:13](/[CH3:14])=[CH:12]\[C:11]([OH:16])=[O:15])=[CH:3]1
Reactant: Sc1c[nH]c2ccccc12
Reactant: CC#CC(=O)O
Product: C/C(=C/C(=O)O)Sc1c[nH]c2ccccc12

Procedure:
By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and tetrolic acid gives 10.2 g of product after recrystallization from acetonitrile, mp 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][OH:14])=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][O:14][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)c2cc(C)c(CO)cc2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(Cl)c2cc(C)c(COC3CCCCO3)cc2n1
Yield: 58.9 %

Procedure:
A solution of (4-chloro-2,6-dimethyl-quinolin-7-yl)-methanol (example 59c, 300 mg, 1.35 mmol), 3,4-dihydro-2H-pyran (342 mg, 4.06 mmol), and pyridinium toluene-4-sulfonate (374 mg, 1.49 mg) in dichloromethane (3 mL) and toluene (3 mL) was stirred at r.t. for 3 d, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) afforded the title compound (243 mg, 59%). White solid, ISP-MS: m/e=306.3 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1ccc(Cl)c(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1-chloro-4-fluorobenzene and isolated as light-yellow gum. MS(m/e): 425.3 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:24]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:25][CH3:26]>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13]([O:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCc1ccc(O)cc1
Reactant: CCCCCCCCC(Br)C(=O)Nc1cccc2cnccc12
Product: CCCCCCCCC(Oc1ccc(CCC)cc1)C(=O)Nc1cccc2cnccc12

Procedure:
N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to the procedures described in Examples 3 and 25, was coupled with 4-propylphenol according to the procedure described in Example 6 to give the title compound.
Reaction SMILES: [CH:1](OCC)=[O:2].Cl.[CH3:7][O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CCO>[CH3:7][O:8][C:9](=[O:13])[CH2:10][N:11]([CH:1]=[O:2])[CH3:12]
Reactant: CCOC=O
Reactant: CNCC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CN(C)C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl formate (850 mL) was added to sarcosine methyl ester HCl salt (205 g, 1.46 mol, grounded into powder prior to use), potassium carbonate (205 g, 1.48 mol), and EtOH (800 mL, stirred overnight at rt, and filtered. The filtrate was concentrated in a rotary evaporator during which the residue separated into two layers. The upper layer was separated and the lower layer was extracted with EA. Combined EA extracts and the upper layer were dried over MgSO4, filtered, and concentrated to yield 185 g (81%) of N-formyl sarcosine methyl ester which was used for the following reaction. NaH (60% oil suspension, 16.0 g, 0.4 mol) was carefully added in several portions in 1 h to a mixture of N-formyl sarcosine methyl ester (50 g, 0.34 mol) and ethyl formate (160 mL) cooled in an ice-water bath. The reaction mixture was stirred, the temperature raised to rt, and the stirring continued overnight. The reaction mixture was triturated twice with hexane (100 mL each time), the residue dissolved in EtOH (100 mL) and concentrated HCl (60 mL), and the reaction mixture stirred at 110° C. After 1 h, the reaction mixture was cooled, filtered, the residue washed with EtOH and the filtrate concentrated to yield a thick brown oil. The oil was added to 10% HOAc in water (200 mL), NH2CN (35 g) and sodium acetate (90 g), stirred at 95° C. After 1 h the reaction mixture was concentrated to ⅓ its original volume in a rotary evaporator and its pH adjusted to about 9 by addition of sodium carbonate. The reaction mixture was then extracted with EA (8×100 mL), the combined EA layers dried, filtered, and concentrated to yield a residue which was purified by recrystallization to yield 1-N-methyl-2-amino imidazole-5-carboxylic acid ethyl ester (“amino ester”).
Reaction SMILES: [C:1]([C:3](=[C:7](OCC)[CH2:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].O>CO>[NH2:2][C:1]1[N:22]([C:15]2[C:14]([Cl:13])=[CH:19][C:18]([Cl:20])=[CH:17][C:16]=2[Cl:21])[N:23]=[C:7]([CH2:8][CH3:9])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCOC(CC)=C(C#N)C(N)=O
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: CO
Product: CCc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Part A: To a stirred solution of 320 mg (1.9 mmol) of 2-cyano-3-ethoxypentenamide in 7 mL of MeOH was added 465 mg (2.2 mmol) of 2,4,6-trichlorophenylhydrazine. The solution was stirred 3 h at reflux, treated with 2 mL of water, and allowed to stir an additional 1 h, cooling to RT. The white solid which precipitated was filtered, washed with 2:1 MeOH-water, and air-dried to afford 520 mg (82%) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, mp 186-188° C., Mass Spec (CI+): 331.9989 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])(=[O:27])[CH3:26]
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reaction time: 48 h

Procedure:
A mixture of 1.8 g. of 4,5-bis(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 25 ml. of acetic anhydride was heated at reflux with stirring under nitrogen for 2 days and then concentrated under vacuum. The residue was purified by chromatography on Silic AR CC-7 (eluting with hexane and then hexane/toluene) to give 400 mg. of a colorless solid product. Recrystallization from ethanol/H2O gave an analytical sample, m.p. 75°-76° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:15][S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)(=[O:18])=[O:17]
Reactant: COc1ccc(N)cc1C1OCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NS(C)(=O)=O)cc1C1OCCO1
Reaction time: 20 h
Yield: 88.1 %

Procedure:
To a solution of 2-(5-amino-2-methoxyphenyl)-1,3-dioxolane (867 mg, 4.4 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (375 μl, 4.84 mmol) and stirred for 20 hr. To the resulted reaction mixture was added water and aqueous NaHCO3, and then extracted with ether/CH2Cl2. The extract was evaporated in vacuo to give crude 2-(5-methylsulfonylamino-2-methoxyphenyl)-1,3-dioxolane (1.06 g, 88.1%) as a slight brown oil.
Reaction SMILES: [Cl:1]/[C:2](/[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:3](\Cl)/[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[NH2:21]/[C:3](/[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])=[C:2](\[Cl:1])/[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: [NH4+]
Reactant: CC(C)OC(=O)/C(Cl)=C(/Cl)C(=O)OC(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)/C(N)=C(/Cl)C(=O)OC(C)C
Yield: 118.7 %

Procedure:
26.9 g (0.1 mol) of diisopropyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. 29.65 g (85.6% yield) of diisopropyl aminochloromaleate were obtained as a reddish-yellow, viscous liquid (purity according to GC analysis 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:23][CH:24]=[CH2:25])[C:13]([NH:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](OC(NC(CC=C)C(O)=O)=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:26]([O:21][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:23][CH:24]=[CH2:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 19 h

Procedure:
N-(N-Benzyloxycarbonyl-2-Amino-4-Pentenoyl)-L-Valine Benzxyl Ester (4) To a cooled (0-5° C.) solution of 24 mg (0.096 mmol) N-(N-benzyloxycarbonyl-2-amino-4-pentenoic acid (3), 36 mg (0.096 mmol) valine benzyl ester p-toluenesulfonyl salt, and 11 μL (0.096 mmol) N-methylmorpholine in 2 mL CH2Cl2 was added 14 mg (0.101 mmol) HOBt and 21 mg (0.101 mmol) DCC and the mixture was stirred for 19 h. The solution was filtered and the filtrate diluted with 10 mL CH2Cl2 and washed with two 10-mL portions of 0.5 N HCl, with two 10-mL portions of saturated aqueous NaHCO3, and with 10 mL brine. The organic phase was dried (MgSO4) and concentrated. The crude product was applied to a silica gel column (1×15 cm) and elution with 5% MeOH in CH2Cl2 gave pure N-(N-benzyloxycarbonyl-2-amino-4-Pentenoyl)-L-valine benzyl ester (4) as a colorless oil: yield 35 mg (83%); 1H NMR (CDCl3) δ0.80-0.90 (m, 6H); 2.14-2.20 (m, 1H); 2.49-2.56 (m, 2H); 4.20-4.32 (M, 1H); 4.55-4.60 (m, 1H0; 5.07-5.30 (M, 6H); 5.65-5.83 (m, 1H); 6.42-6.49 (m, 1H); 7.30-7.34 (m, 10H); mass spectrum (CI, methane) m/z 439 (M+H)+, 225.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][CH2:41][OH:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][CH:41]=[O:42])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.4 %

Procedure:
To a solution of the compound of example 5, step 5 (0.955 g, 1.67 mmol) in 10 ml of DCM under argon was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.78 g, 1.84 mmol). The mixture was stirred at room temperature for 3.5 h and then diluted with 40 ml of diethyl ether. The solution was washed three times with a 1 N solution of sodium hydroxide (15 ml) and twice with brine (15 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 0.965 g of the title compound as a green powder which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:14][C:13]([C:6]1[NH:7][C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:15]
Reactant: O=C(O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1

Procedure:
To the obtained 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid were added methanol (400 ml) solution and sulfuric acid (40 ml) and the mixture was refluxed for 20 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give the title compound (6.51 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11]N3CCN(S(C)(=O)=O)CC3)[S:8][C:6]=2[N:7]=1.ClC1N=C(N2CC[O:41]CC2)C2C=CSC=2N=1.[Li]CCCC.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH:11]=[O:41])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -60 °C

Procedure:
Scheme 7 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 by formylation of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 in THF at −78° C. with n-BuLi in hexanes (1.2 equiv.). The resulting slurry was allowed to warm up to −60° C., cooled to −78° C. and DMF (1.5 equiv.) was added slowly to afford 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19. To a suspension of 19, 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 1.45 equiv.) and anhydrous sodium acetate in 1,2-dichloroethane was added trimethyl orthoformate (10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours, then sodium triacetoxyborohydride was added and the reaction was stirred for 24 hours to give 20.