Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:28]=2[CH2:27][CH2:26]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:28]=2[CH2:27][CH2:26]1
Reactant: [N-]=[N+]=NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (0.71 g) was added to a solution of 3-(2-azidoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.68 g) in dry tetrahydrofuran under a nitrogen atmosphere and the reaction mixture was then stirred at room temperature for 18 hours and heated at 50° for 5 hours. After cooling, water was added and the mixture was stirred at room temperature for 3 days. The solvent was then evaporated in vacuo and the residue was diluted with 2M hydrochloric acid and washed three times with ethyl acetate. The aqueous layer was made alkaline (pH=12) with 5M sodium hydroxide and extracted three times with ethyl acetate. The latter organic extracts were combined and dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil, yield 0.56 g, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:27]([OH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:21]([OH:26])=[O:34].[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1cccnc1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)C(F)(F)F
Product: O=c1onc(-c2nonc2NCc2cccnc2)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.6 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (50 mg, 0.11 mmol), nicotinyl alcohol (14 μL, 0.15 mmol), and triphenylphosphine (42 mg, 0.16 mmol) in tetrahydrofuran (0.35 mL) at 0° C. was treated with diisopropyl azodicarboxylate (34 pt, 0.17 mmol). The reaction mixture was stirred at 25° C. for 16 h and purified by preparative LCMS to give the desired product (4 mg, 6%). LCMS for C16H11BrFN6O3 (M+H)+: m/z=432.9, 434.9.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[C:27]([OH:29])=[O:28])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:31][O:28][C:27]([C@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]1[S:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:16])=[O:17])=[O:29]
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 335.8 %

Procedure:
A solution of the title A compound, (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (5.55 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmol) in methanol (260 mL) is heated under nitrogen at reflux for 4 hours. The solution is allowed to stand overnight at room temperature which results in the formation of a crystalline solid. The crystals are collected by vacuum filtration and dried at high vacuum. A second crop of crystals is obtained from the mother liquor that is isolated and dried at high vacuum. A combined yield of 3.84 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester is obtained as a pure crystalline product: [M+1]+=424.27.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1)#[N:12].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=1.P(OCC)(OCC)(OCC)=O>C1COCC1.C(OCC)(=O)C>[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[C:2]([C:1]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])=[C:3]([CH3:5])[N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:37])[F:24])[CH:27]=3)[C:33](=[O:34])[NH:35]2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1)#[N:12]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C=CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The reaction was carried out under argon. Allyl acetoacetate (5.94 g, 41.5 mmol; 1.0 eq.) was initially charged in THF (117 ml) at RT. Subsequently, 4-cyano-2-nitrobenzaldehyde (10.45 g, 41.5 mmol, purity 70%; 1.0 eq.), 1-[3-(trifluoromethyl)phenyl]urea (8.48 g, 41.5 mmol) and triethyl phosphate (17.7 g) were added. The mixture was stirred under reflux for 16 h. For work-up, initially ice-water was added, and the mixture was then taken up in ethyl acetate (400 ml). The organic phase was dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from hot water/isopropanol (2:1, ˜400 ml). The solid obtained was triturated with diethyl ether (60 ml), once more filtered off with suction, washed with a little diethyl ether and dried under high vacuum. The title compound was obtained as a solid (16.63 g, 82% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=1>N1C=CC=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CCN(S(=O)(=O)c3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 1-(4-nitrophenyl)-piperazine (2.50 g, 12.1 mmol) in pyridine (15 mL) was added a solution of pyridine-3-sulfonyl chloride (2.78 g, 15.7 mmol) in THF (30 mL) under an argon atmosphere at 0° C. The reaction was warmed to r.t. and stirred for 2 h, before the mixture was evaporated to dryness. The residue was partitioned between water and dichloromethane, the organic layer separated and washed successively with sat. sodium bicarbonate solution, water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was subjected to column chromatography over neutral alumina using 5% to 70% ethyl acetate in petroleum ether as eluent to afford 1-(4-nitrophenyl)-4-(pyridine-3-sulfonyl)-piperazine (1.63 g, 39%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[I:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[NH:15][N:14]=1>N1CCCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:22]\[C:18]1[CH:17]=[C:16]2[C:21]([C:13]([I:12])=[N:14][NH:15]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(F)cc2/C1=C/c1ccc2c(I)n[nH]c2c1
Temperature: 60 °C
Yield: 97.1 %

Procedure:
A round bottom flask was charged with 5-fluoroindolin-2-one (100 mg, 0.661 mmol), 3-iodo-1H-indazole-6-carbaldehyde (180 mg, 0.661 mmol), piperidine (13 uL, 0.027 mmol) and methanol (7.5 mL). The reaction was then heated to 60° C. for 3 h prior to cooling the reaction mass to room temperature. Filtration and washing with methanol (0.50 mL×2) gave the title compound as a yellow solid (260 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.72 (s, 1H), 9.00 (s, 1H), 8.06 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.71 (s, J=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.81 (d, J=4.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[OH:20][CH:21]([CH2:24][OH:25])[CH2:22][NH2:23]>CN(C)C=O.O>[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:23][CH2:22][CH:21]([OH:20])[CH2:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: NCC(O)CO
Reactant: Clc1ccc(-c2nc(Cl)c3ccccc3n2)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: OCC(O)CNc1nc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
A mixture of 46.5 g. (0.15 mole) of 4-chloro-2-(3,4-dichlorophenyl)quinazoline in 500 ml of dimethylformamide and 29 g (0.31 mole) of 2,3-dihydroxypropylamine was heated on a steam bath with stirring for 4 hrs. Diluted the mixture with water until turbid and cooled in an ice bath. The colorless solid was filtered and recrystallized from methyl alcohol (Darco). The product was collected as colorless needles melting at 155°-160° (with previous softening) in a yield of 49 g. (90%). Further recrystallization from nitromethane gave 39 g. melting at 162°-164°. Anal. Calcd. for C17H15Cl2N3O2 : C, 56.06; H, 4.15; N, 11.54 Found: C, 55.63; H, 4.04; N, 11.49.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][NH:18][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=4)[C:10](=[O:17])[N:11]=3)=[CH:28][C:25]=2[C:26]#[N:27])=[CH:31][C:32]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.1 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.201 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(4-chloro-3-trifluoromethyl-phenoxy)-benzonitrile (110 mg, 1.6 eq) were heated in a sealed vial at 130° C. for 20 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/20% MeOH in DCM solvent system (gradient 5-50% of 20% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with cyclohexane and diethyl ether to obtain 2-(4-chloro-3-trifluoromethyl-phenoxy)-5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-benzonitrile (36 mg, yield=29.7%, purity=90%) in form of tain coloured powder. MS: [M+H]+=541.34. 1H NMR (300 MHz; CDCl3) δ/ppm 2.65 (s, 3H), 2.94 (t, J=7.02 Hz, 2H), 3.57 (s, 2H), 3.59-3.68 (m, 2H), 5.49 (br.s., 1H), 6.89 (d, J=8.61 Hz, 1H), 7.15 (dd, J=8.30 Hz, J=2.98 Hz, 1H), 7.38 (d, J=2.76 Hz, 1H), 7.44 (dd, J=8.82 Hz, J=1.91 Hz, 1H), 7.51 (d, J=8.51 Hz, 1H), 7.60 (d, J=2.02 Hz, 1H), 7.71 (s, 1H), 8.53 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[CH:11][CH2:12]O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.[NH2:23][C:24]1[S:25][C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:32]=2[N:33]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:23][C:24]1[S:25][C:26]2[CH2:27][CH2:28][N:29]([CH2:12][CH:11]=[CH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)[CH2:30][CH2:31][C:32]=2[N:33]=1
Reactant: OCC=Cc1ccc2[nH]ccc2c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc3[nH]ccc3c1)CC2
Temperature: -5 °C
Reaction time: 15 h

Procedure:
At -15° C., a solution of 63 mg (0.55 mmol) of methanesulphochloride in 6 ml of chloroform is added dropwise to a stirred solution of 95 mg (0.55 mmol) of 3-(5-indolyl)allyl alcohol and 142 mg (1.10 mmol) of N-ethyl-N,N-diisopropylamine in 6 ml of anhydrous methylene chloride and the resulting mixture is stirred for 15 hours at -5° C. It is evaporated down in vacuo at 20° C., the evaporation residue is dissolved in 3 ml of anhydrous dimethylformamide, 370 mg (2.20 mmol) of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine are added and the mixture is stirred for 4 hours at 50° C. and for 3 hours at 70° C. The mixture is then evaporated down in vacuo, distributed between chloroform and water and the dried and filtered chloroform solution is evaporated down in vacuo. The evaporation residue is purified by triple column chromatography on neutral aluminium oxide (toluene/ethyl acetate/ethanol=4:1:0.5). Yield: 8 mg (4.5% of theory), Melting point: 60°-65° C. (foamy). Molecular peak (m/z) Calculated: 324 Found: 324
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:23])([CH3:22])[C:7](=[O:21])[N:8]2[C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH3:23])([CH3:22])[C:7]2=[O:21])=[O:12])[CH2:16][CH2:17]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)C(=O)N(C(=O)NCC2CCNCC2)c2cc(F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCC(CNC(=O)N2C(=O)C(C)(C)c3ccc(F)cc32)CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A solution of 6-fluoro-3,3-dimethyl-2-oxo-N-(piperidin-4-ylmethyl)indoline-1-carboxamide (200 mg, 0.63 mmol, step 2 in Example 17) and triethylamine (114 μL, 0.82 mmol) in tetrahydrofuran (3 mL) was stirred at 0° C., it was slowly added tert-butyl bromoacetate (111 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 5 h and at 35° C. for 4 h. It was further added triethylamine (17 μL, 0.12 mmol) and tert-butyl bromoacetate (18 μL, 0.12 mmol). The solution was stirred at room temperature overnight. The resulting solution was added sat. sodium bicarbonate. It was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with ethyl acetate/hexane (1:10 to 1:6) to give 203 mg (74%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:31][C:12]2=[N:13][C:14]([CH3:30])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3OC)[N:11]2[CH:10]=1.[CH2:32]([O:34]CC)C>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:31][C:12]2=[N:13][C:14]([CH3:30])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:34][CH3:32])=[CH:19][CH:18]=3)[N:11]2[CH:10]=1
Reactant: CCOC(=O)C1=C(C)N=C2SC(c3c(Cl)cccc3Cl)=CN2C1c1ccccc1OC
Reactant: CCOCC
Product: CCOC(=O)C1=C(C)N=C2SC(c3c(Cl)cccc3Cl)=CN2C1c1ccc(OC)cc1
Product: Cl
Yield: 79 %

Procedure:
1.82 g (3.83 mmol) of ethyl (RS)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate were dissolved in 20 ml of methanolic hydrochloric solution (2.6N) while stirring and treated with 100 ml of diethyl ether. After 15 h. the crystals were filtered off. There were obtained 1.55 g (79%) of ethyl (RS)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate hydrochloride as a light yellow solid with m.p. 233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:14]([O:16][CH3:17])=[O:15])#[C:9][C:10]([O:12][CH3:13])=[O:11]>CO>[NH:1](/[C:9](=[CH:8]\[C:14]([O:16][CH3:17])=[O:15])/[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(\Nc1ccccc1)C(=O)OC

Procedure:
Purified aniline (15.0 g, 0.16 mole) was reacted with dimethyl acetylenedicarboxylate (19.8 ml, 0.15 mole) in 400 ml methanol according to the procedure of Heindel, et.al., J. Het. Chem. 1966, 3, 222. The reaction was refluxed for 18 hours, then worked up by evaporating the solvent, dissolving the residue in ether, and washing consecutively with 0.5 N HCl, H2O, and sat. NaCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel in 80/20 hexane/EtOAc which yielded 29.14 of the Michael Adduct, dimethyl anilinofumarate as a light yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][CH2:26][Mg+].[Br-]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11](=[O:12])[CH2:25][CH3:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
tert-butyl 3-(tert-butyldimethylsilyloxy)-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (22a) (1.5 g, 4.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by THF (33 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of EtMgBr in THF (12.0 mL, 12.0 mmol, 3.0 equiv.) was added over 10 min. The reaction stirred for 30 min 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 (33 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (20 mL) and extracted with EtOAc (3×40 mL). The organic layers were washed with sat. NaCl (2×30 mL) and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 1.4 g of crude material. The residue was purified by flash column chromatography (10% EtOAc/hexanes) to give 1.1 g (86%) of 26 as a clear oil. Rf=0.25 (10% EtOAc/hexanes); IR (film) 3431, 3371, 2975, 2953, 2930, 2883, 2856, 1711, 1492, 1172, 838 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.45 (d, J=7.0 Hz, 1H, carbamate-NH), 4.22 (m, 1H, Boc-NH—CH), 4.00 (dd, J=10.0, 3.5 Hz, 1H, CH—CH2), 3.76 (dd, J=10.0, 4.0 Hz, 1H, CH—CH2), 2.56 (m, 1H, O═C—CH2), 2.44 (m, 1H, O═C—CH2), 1.39 (s, 9H, Boc-tbutyl-CH3), 1.08 (t, J=7.0 Hz, 3H, O═C—CH2CH3), 0.79 (s, 9H, Si-t-butyl-CH3), −0.03 (s, 6H, Si—CH3); 13C NMR (125 MHz, CDCl3) δ 208.5, 155.5, 79.7, 63.6, 61.2, 33.5, 28.4, 25.8, 18.2, 7.5, −5.5, −5.5; LRMS (ESI-MS m/z): Mass calcd for C16H33NO4Si [M]+, 331.52. Found 332.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:5]2[C:4]=1O)#[N:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=2)[N:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Product: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Temperature: 75 °C
Yield: 48 %

Procedure:
To a round bottom flask was added POCl3 (200 mL) and ethyl 3-cyano-4-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (20 g, 80 mmol). The reaction was heated under nitrogen at 75° C. for 2 hours. The reaction was cooled to room temperature and POCl3 was removed under vacuum. The residue was poured onto ice-water. The aqueous solution was extracted with CH2Cl2. The organic layer was washed with saturated sodium carbonate solution, dried and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 10 g (48%) of the title compound as a yellow solid. H1 NMR (400 MHz, CDCl3) δ ppm: 8.33 (1H, d, J=1.3 Hz), 8.11 (1H, s), 7.41 (1H, d, J=1.6 Hz), 4.41 (2H, q, J=6.8 Hz), 1.41 (3H, t, J=6.8 Hz).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:17])[O:15][C:14](=[O:16])[CH2:13][CH2:12]2)=[C:7]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C(Cl)Cl.O.[CH2:27](O)[CH3:28]>>[CH3:17][C:11]1([CH2:12][CH2:13][C:14]([O:15][CH2:27][CH3:28])=[O:16])[C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2
Reactant: CC1(c2ccsc2-c2cccs2)CCC(=O)O1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCC1(C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.30 mL) was added dropwise to a solution of 5-([2,2′-bithiophen]-3-yl)-5-methyldihydrofuran-2(3H)-one (0.030 g, 0.11 mmol) in ethanol (2 mL) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent dichloromethane) to afford a pure dark yellow oil (IIv) (0.0106 g, 31.9%). 1H-NMR (CDCl3): δ=7.15 (d, J=4.9 Hz, 2H), 6.93 (d, J=4.7 Hz, 2H), 3.96 (q, J=7.1 Hz, 2H), 2.28-2.21 (m, 2H), 1.80-1.74 (m, 2H), 1.45 (s, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][OH:6])#[N:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>ClCCl>[CH3:30][S:31]([O:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC#N
Reactant: CS(=O)(=O)Cl
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COS(C)(=O)=O

Procedure:
A mixture of 940 mg (2.29 mM) of 2-cyanomethyl-3-octadecylcarbamoyloxypropanol V n2, 0.231 ml (2.98 mM) of methanesulfonyl chloride and 0.483 ml (3.44 mM) of triethylamine in 10 ml of dichloromethane is allowed to react by the same procedure as described in (52) and crude product of the titled compound V n2a is obtained.