Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C@:16]([NH:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])([C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])[C@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:15])[CH3:14].[CH2:53]=[O:54]>C1COCC1>[Si:40]([O:39][C@H:37]([C@@:16]([NH:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])([C:13](=[O:15])[CH2:14][CH2:53][OH:54])[C@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:38])([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:42]
Reactant: CC(=O)[C@](NC(=O)N(C)C)([C@H](C)O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/c1ccccc1)NC(=O)OCc1ccccc1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](NC(=O)N(C)C)(C(=O)CCO)[C@@H](/C=C/c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame-dried 250-mL round-bottomed flask was charged with diisopropylamine (5.8 mL, 41.3 mmol, 3.5 equiv) and THF (100 mL). The resulting solution was cooled to 0° C. and n-butyllithium (1.65 M in hexanes, 25.0 mL, 41.3 mmol, 3.5 equiv) was added dropwise. The reaction was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of ketone 6 (6.8 g, 11.8 mmol, 1.0 equiv) in THF (25 mL) was added dropwise, and the resulting mixture was stirred for 45 min and warmed to −45° C. Formaldehyde gas (CH2O(g), prepared by heating paraformaldehyde ((CH2O)n, 5.0 g, 166.7 mmol, 14.1 equiv) to 145° C. under a positive pressure of nitrogen) was bubbled through the reaction. The reaction was stirred at −45° C. until full conversion to product was indicated by TLC analysis, typically 1 h. The reaction was quenched by the addition of a saturated NH4Cl(aq.) (30 mL), and the resulting mixture was extracted with Et2O (3×30 mL). The combined organic extracts were dried with magnesium sulfate and concentrated in vacuo. The crude product was purified via flash chromatography (50:50 to 60:40 EtOAc:hexanes) to give alcohol 8 as a clear, viscous oil (4.9 g, 70%). Analytical data: [α]D19+11.2 (c=1.00, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.35-7.26 (m, 10H), 7.21 (t, J=7.0 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0, 9.0, 1H), 5.32 (s, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.02 (d, J=12.0 Hz, 1H), 4.98 (t, J=8.5 Hz, 1H), 4.40 (q, J=6.5 Hz, 1H), 3.85-3.82 (m, 1H), 3.73-3.71 (m, 1H), 2.93 (s, 6H), 2.82-2.70 (m, 2H), 1.23 (d, J=6.5 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 208.5, 158.7, 155.9, 136.8, 136.6, 132.3, 128.4, 128.3, 128.1, 127.9, 127.5, 127.1, 126.6, 74.2, 71.7, 66.6, 58.1, 55.2, 40.7, 36.6, 25.7, 19.2, 17.8, −3.7, −5.0; LRMS (ESI+) Calcd. for C32H47N3O6Si+H, 598.33. Found, 598.32. IR (thin film, cm−1) 3429, 2954, 1716, 1646, 1507, 1252, 966, 695, 530; TLC (50:50 hexanes:EtOAc): Rf=0.20.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.[Br:22][C:23]1[N:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1>>[Br:22][C:23]1[N:28]=[CH:27][C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[CH:25][N:24]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Brc1cnc(Br)nc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cnc(Br)nc2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2,5-dibromo-pyrimidine.
Reaction SMILES: CN(C)C=O.[C:6]([OH:19])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)([Cl:22])=O>>[C:6]([Cl:22])(=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Cl

Procedure:
82.2 g (1.13 mol) of N,N-dimethylformamide were added to 4.5 mol of lauric acid in a stirred apparatus. The reaction solution was brought to a temperature of from 40 to 50° C. with stirring, and a total of 5.06 mol of gaseous phosgene were introduced under atmospheric pressure. After the addition of phosgene was complete, the two phases were separated from one another. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of 0.50. The carbonyl chloride phase comprised 99.1 area % of lauroyl chloride and 0.15 area % of lauric acid. The color number was 268 APHA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)c(Br)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCc1ccc(C#N)c(Br)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-bromo-4-cyanophenyl)ethyl]amino}ethyl)carbamate (30 mg, 0.081 mmol) and TEA (30 mg, 0.30 mmol) in DCM (1 mL) was added chloroacetyl chloride (10 mg, 0.089 mmol) to the mixture at 0° C. The mixture was stirred at RT for 0.5 hour. Then the residue was diluted with DCM (20 mL) washed with water (5 mL×2) dried over Na2SO4 and concentrated in vacuo to give the desired product. MS m/z: 444 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)S(N)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccccc1)c1cc(Br)ccc1N

Procedure:
A solution of (2-Amino-5-bromo-phenyl)-phenyl-methanone (67 g, 244 mmol), 2-Methyl-propane-2-sulfinic acid amide (35.38 g, 292 mmol) and Ti(OEt)4 (111.15 g, 487 mmol) in THF (800 mL) is heated to reflux overnight. Then H2O is added and filtered and concentrated. The residue is purified by chromatography on silica gel to give desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO>[CH3:19][O:12][C:11]([C:9]1[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CCC(CC)n1c(C(=O)OC)cc2cnc(Cl)nc21
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (13 mg, 0.049 mmol) in MeOH (0.5 mL) is added (trimethylsilyl)diazomethane (0.07 mL of a 2.0 M in hexanes). The reaction mixture is stirred for 2 h and concentrated in vacuo to give 13 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester. The crude product is used as it is.
Reaction SMILES: F[C:2](F)(F)[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#[N:6].[CH:31](O)(C)[CH3:32]>>[CH:2]1([C@H:3]([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4][C:5]#[N:6])[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Reactant: CC(C)O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C4CC4)c3)ncnc21
Reaction time: 0.18 h
Yield: 94 %

Procedure:
A slurry of 1.5 Kg of 20-micron Chiralcel® OD chiral stationary phase (CSP) made by Daicel in 3.0 L of isopropanol (IPA) was packed into a PROCHROM Dynamic Axial Compression Column LC110-1 (11 cm ID×25 cm L; Column Void Vol.: approximate 1.5 L) under 150 bar of packing pressure. The packed column was then installed on a Novasep Hipersep HPLC unit. The column and HPLC system were flushed with methanol (17 L) and the mobile phase made by a mixture of isopropanol and hexane (2:8 by volume, 17 L). The feed solution was then prepared by dissolving 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, racemic SEM-protected compound, 3100 g, 7.1 mol) in the mobile phase to a concentration of 120 g/L. The feed solution (120 mL per injection) was then sequentially injected into the preparative HPLC chiral column for separation. The chiral column was eluted with the mobile phase at a flow rate of 570 mL/min at room temperature. The column elution was monitored by UV at wavelength 330 nm. Under these conditions, a baseline separation of the two enantiomers was achieved. The cycle time for each injection was 11 minutes and a total of 210 injections were performed for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-34) and Peak 2 (the desired (R)-enantiomer, (R)-34) were collected separately from each injection, and fractions collected for each peak were continuously concentrated at 40° C. under reduced pressure (40-120 bar). The residue from each evaporator was further dried under high vacuum to constant weight to afford (3R)-3-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-34, 1457 g, 1550 g theoretical, 94%) from Peak 2 as a light yellow oil which solidified upon standing at room temperature in vacuo and (3S)-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((S)-34, 1488 g, 1550 g theoretical, 96%) from Peak 1 as an yellow oil which solidified upon standing at room temperature in vacuo.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[N:23](C=O)[NH:22]2)=[C:5]([F:29])[CH:4]=1>CO.CC(C)=O>[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][NH:22]2)=[C:5]([F:29])[CH:4]=1
Reactant: O=Cn1[nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)sc1=O
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O=c1[nH][nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)s1
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
A solution of 10% hydrochloric acid in methanol (8 ml) was added to a solution of 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-3-formyl-1,3,4-thiadiazolidin-2-one (33 g) in acetone (60 ml). After stirring for 0.5 hour, the solvents were removed and the residue processed. A minimal amount of ethanol was used to dissolved the residue and hexane added to induce crystallization. The crystals were filtered off and dried to give the product (1.0 g, 36%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:16](=[O:17])[NH:15][C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1.I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[Br:3][C:4]1[C:16](=[O:17])[N:15]([CH:19]([CH3:21])[CH3:20])[C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Temperature: 46 °C
Yield: 59.4 %

Procedure:
To a suspension of NaH (120 mg, 5.00 mmol) in DMF (15 mL) was added 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (572 mg, 2 mmol). The mixture was heated to 46° C. The solution was cooled down slightly and 2-iodopropane (0.30 mL, 3.0 mmol) was added. The mixture was heated at 46° C. for 30 min and then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and concentrated. The crude product was purified by silica gel flash chromatography, using EtOAc/Hexane, to give the title compound (390 mg, 59%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][Si](C(C)(C)C)(C)C)=[C:6]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH2:9][O:8][C:7]2=[O:16])[CH:2]=[CH2:3].[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27]>C(O)(=O)C>[C:26]([O:17][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:12]([O:13][CH3:14])[C:11]([CH3:15])=[C:10]2[C:6]=1[C:7](=[O:16])[O:8][CH2:9]2)(=[O:27])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: C=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: CC(=O)O
Product: C=CCc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of 5-allyl-4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran [(J. W. Patterson and G. Huang, Chemical Communications, 1579 (1991)](7.5 g) in acetic acid (95 ml) and acetic arthydride (95 ml) was refluxed for 18 hours, then cooled and poured into ice water. The solution was extracted with ethyl acetate, and the extract washed with dilute aqueous sodium bicarbonate, followed by water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give 4-acetoxy-5-allyl-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran, mp 101°-102° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][N:2]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)Cc1cnccn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1cnccn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrazin-2-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 159, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrazin-2-yl)acetamido)propanamide (66 mg, 46%). 1H-NMR (400 MHz, CDCl3): σ 8.63-8.44 (m, 4H), 7.40-7.19 (m, 9H), 7.05-6.92 (m, 3H), 4.74-4.70 (m, 1H), 4.66 (d, 1H), 4.55 (d, 1H), 4.10 (dd, 1H), 3.85 (s, 2H), 3.64 (dd, 1H). MS (EI) for C28H25FN4O4. found 501.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1cccnc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccnc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=146-157° C.). The reaction was monitored by tlc (Rf=0.1 in CHCl3/MeOH 98:2) and the product was purified by silica gel chromatography using 959:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([C:6](=[CH:12][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCCC(=O)C(=CNc1ccccc1)C(=O)OCC
Yield: 68.9 %

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (95 g, 0.4 mol) and aniline (36 ml, 0.4 mol) was heated at reflux for 30 minutes, then cooled, diluted with petroleum ether, and left to crystallise at -20° overnight. Filtration and washing gave ethyl 2-butyryl-3-(phenylamino)acrylate (72 g, 60%) as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([CH3:6])([CH3:5])[CH:3]1[NH:7][C:8]([NH2:10])=[S:9].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1([CH3:11])[C:4]([CH3:5])([CH3:6])[CH:3]1[NH:7][C:8]1[S:9][C:13]2([C:17](=[O:18])[N:10]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: CC1(C)C(NC(N)=S)C1(C)C
Reactant: CCOC(=O)C1(Br)CCC1
Product: CC1(C)C(NC2=NC(=O)C3(CCC3)S2)C1(C)C

Procedure:
Synthesis was performed from N-(2,2,3,3-tetramethylcyclopropyl)thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Fc1ccc(CNc2nc(-c3cccnc3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH2:18][OH:19])[CH2:16][C:15]3[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH3:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)=[O:31]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH2:18][OH:19])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH3:28])=[O:31])=[N:33][CH:34]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO)nc(N)n2)CC1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(CO)C3)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 49A starting from {2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-7-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl}methanol and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Frontier, Cat. No. M10074). LCMS (M+H)+: m/z=489.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=[N+]([O-])c1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(piperidin-4-yl)-1H-indole (0.49 g, 2.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.40 g, 2.1 mmol). The product was isolated as a yellow crystalline solid. Yield 0.34 g (37%). mp 212-214° C. FDMS m/e=434 (M+ of free base).
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC(O[N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:86].[Na+].[Na+].[Na+].[Na+].[C:91]([CH2:94][CH2:95][CH2:96][CH2:97][C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][C:99]=1/[C:104](=[CH:129]\[CH:130]=[C:131]1\[N:132]([CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150])[C:133]2[C:138]([C:139]\1([CH3:141])[CH3:140])=[CH:137][C:136]([S:142]([O-:145])(=[O:144])=[O:143])=[CH:135][CH:134]=2)/[CH:105]=[CH:106]/[C:107]1[C:115]([CH3:117])([CH3:116])[C:114]2[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:120])=[O:119])[CH:113]=2)[N+:108]=1[CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])([OH:93])=[O:92].[Na+].[Na+].[Na+]>>[CH3:117][C:115]1([CH3:116])[C:114]2[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:119])=[O:120])[CH:113]=2)[N:108]([CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])/[C:107]/1=[CH:106]/[CH:105]=[C:104](\[C:99]1[CH:100]=[CH:101][CH:102]=[CH:103][C:98]=1[CH2:97][CH2:96][CH2:95][CH2:94][C:91]([O:93][N:78]1[C:82](=[O:83])[CH2:81][CH2:80][C:79]1=[O:84])=[O:92])/[CH:129]=[CH:130]/[C:131]1[C:139]([CH3:140])([CH3:141])[C:138]2[C:133](=[CH:134][CH:135]=[C:136]([S:142]([O-:145])(=[O:144])=[O:143])[CH:137]=2)[N+:132]=1[CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150].[Na+:86].[Na+:86].[Na+:86]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccccc2CCCCC(=O)O)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccccc2CCCCC(=O)ON2C(=O)CCC2=O)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 34 is prepared analogously to compound 9 (Example 9), except that compound 33 is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].C(OC(=O)C)(=O)C.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([CH:33]=O)[N:32]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:33][C:31]1[N:32]=[C:28]([CH3:27])[S:29][CH:30]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccccc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (10 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-2-methyl-3H-quinazolin-4-one (0.135 g, 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed for 3 hours, and was then allowed to cool to ambient temperature. Once the reaction had cooled to abient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, dried over sodium sulfate and then concentrated to yield a waxy tan solid. This residue was triturated with ether, filtered and dried to afford 0.139 g (73%) of 3-(2-chloro-phenyl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.