Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH2:3].[N:4]([C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[C:5]=[O:6]>O1CCCC1>[CH3:1][O:2][NH:3][C:5]([NH:4][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:6]
Reactant: CON
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: C1CCOC1
Product: CONC(=O)Nc1cc(C(C)(C)C)on1

Procedure:
8.5 g of methoxyamine was added very slowly to a stirred solution of 15 g of 4A in 600 ml of tetrahydrofuran. The resulting mixture was filtered and the solid was triturated with ether to give 1-methoxy-3-(5-(tertiary-butyl)-1,2-oxazol-3-yl)urea (4B), m.p.: 145°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: COCCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: COCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 46.7 %

Procedure:
A solution of the product of Example 48 (150 mg, 0.34 mmol) and 2-methoxy-ethylamine (0.09 mL, 1.01 mmol) in DMP (2 mL) was stirred 23° for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material, which was purified as described in Example 198 to give the desired product 70 mg (47%). LC-MS: 441.2 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[F:23][C:24]1([F:33])[CH2:27][N:26]([C:28](=[O:32])/[CH:29]=[CH:30]\I)[CH2:25]1.O>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][N:16](/[CH:30]=[CH:29]/[C:28]([N:26]3[CH2:27][C:24]([F:33])([F:23])[CH2:25]3)=[O:32])[C:15](=[O:18])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=1
Reactant: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1/C=C/C(=O)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (0.5 g, 1.0 eq.) was dissolved in DMF (5 mL) and cooled to 0° C. A solution of NaH in DMF (0.133 g, 2.0 eq.) was added at 0° C. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.689 g, 1.5 eq.) was then introduced. The reaction mixture was stirred for 30 min at room temp. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.502 g of crude product, which was purified by chromatography (1% Methanol in DCM) to give 0.030 g of (E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-one (Yield 4.03%). 1H NMR (400 MHz, CDCl3) δ 8.15-8.19 (d, J=14 Hz, 1H), 7.69-7.87 (m, 3H), 5.27-5.31 (d, J=14 Hz, 1H), 4.05-4.47 (m, 4H), 3.89-3.93 (s, 1H), 3.73-3.77 (s, 1H), 3.60-3.62 (s, 1H), 3.08-3.13 (s, 1H), 2.78-2.90 (s, 1H); LCMS calcd. for C18H14F8N2O2 [M+H]+. found 443.44 at retention time 2.97 min.
Reaction SMILES: O=C(Cl)[O:3][C:4]([Cl:7])(Cl)Cl.[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=2[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][N:17]([C:4]([Cl:7])=[O:3])[CH2:18][CH2:19][C:13]=2[CH:12]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC)CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCN(C(=O)Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.2 mL (10 mmol/1 eq.) of diphosgene in 20 mL of dichloromethane, at about 0° C., there are added, dropwise, a solution of 3.55 g (20 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 22 mL of dichloromethane, and then 4.2 mL (30 mmol/1.5 eq.) of triethylamine. Stirring overnight at ambient temperature and then concentration are carried out. The residue is taken up in dichloromethane, washed with water and dried over magnesium sulphate to yield, after concentration, the desired product.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N:6]1([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[Cl:1][CH2:2][C:3]([N:9]1[CH2:10][CH2:11][N:6]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH2:7][CH2:8]1)=[O:4]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
Chloroacetyl chloride (1.16 ml, 14.62 mmol) is added to an ice-cooled solution of 2-(1-piperazinyl)pyrimidine (2.0 g, 12.18 mmol) in dichloromethane (20 ml) and triethylamine (5.09 ml, 36.54 mmol), and the mixture is stirred for 5 minutes and then warmed to room temperature. After 30 min at RT, water (50 ml) is then added to the mixture, which is extracted twice with methylene chloride (50 ml). The organic phase is washed with saturated sodium chloride solution. Drying of the organic phase over sodium sulphate, filtration, concentration under reduced pressure and silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=10:1 to 1:1) gives 2.05 g (70%) of product as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2>Br>[BrH:1].[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2
Reactant: COc1ccc2nc(C)ccc2c1Br
Agent: Br
Product: Cc1ccc2c(Br)c(O)ccc2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 182.3 %

Procedure:
A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48% HBr (135 mL) was heated to reflux for 7 hours then cooled to 5° C. in 1 hour to give a brown and thick slurry. The slurry was stirred at 0–5° C. for 1 hour then filtered, washed with EtOAc (2×50 mL) and dried in a vacuum oven to give 34.9 g (92%) of the title compound as a brown solid: 1H NMR (DMSO) δ 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H); 13C NMR (DMSO) δ 155.7, 152.0, 142.8, 133.3, 128.9, 126.4, 123.3, 121.2, 103.3, 24.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.CS(Cl)(=O)=O.[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15][F:37])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCF)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (152 mg, 0.404 mmol) obtained in Example 29 was dissolved in dichloromethane (4 ml), followed by the addition of N-methylmorpholine (58.0 μl, 0.528 mmol) and methanesulfonyl chloride (37.8 μl, 0.487 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours, and then at room temperature for further 3 hours. After dilution with dichloromethane, the mixture was successively washed with a saturated aqueous solution of ammonium chloride, water and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was dissolved in tetrahydrofuran (4 ml). To the resulting solution was added a tetrahydrofuran solution (1.0M, 0.487 ml, 0.487 mmol) of tetrabutylammonium fluoride at room temperature. The resulting mixture was stirred at 60° C. for 4 hours. After cooling to room temperature and dilution with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated. The solid thus obtained was recrystallized from hexane, whereby the title compound (30.3 mg, 0.0804 mmol, 20%) was obtained as colorless plate crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]3([CH2:78][CH2:77][CH2:76][CH2:75]3)[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[OH:79][B:72]1[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:28])([F:29])[F:30])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]=2[C:74]2([CH2:75][CH2:76][CH2:77][CH2:78]2)[O:73]1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)B(O)OC21CCCC1)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) can be stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxa-borole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:29]([CH:30]=1)[C:9]1[N:10]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[C:11](=[O:19])[C:12]3[C:17]([C:8]=1[N:7]=2)=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=3.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:29]([CH:30]=1)[C:9]1[N:10]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[C:11](=[O:19])[C:12]3[C:17]([C:8]=1[N:7]=2)=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=3
Reactant: COc1ccc2nc3c4c(C)cccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: Br
Product: Cc1cccc2c(=O)n(-c3ccc([N+](=O)[O-])cc3)c3c(nc4ccc(O)cn43)c12
Yield: 18.5 %

Procedure:
A suspension of 9-methoxy-1-methyl-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo-[4,5-c]isoquinolin-5(6H)-one (I30) (0.14 mmol, 0.056 g) in a concentrated aqueous HBr solution (5 ml) was refluxed overnight. The reaction mixture was concentrated under reduced pressure. The crude product was brought on a filter and washed with isopropanol and isopropylether to give the hydrobromide salt of 9-hydroxy-1-methyl-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (110) (0.010 g, yield=17%, purity (LC)=91%).
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.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][C:52]([F:55])([F:54])[F:53]>>[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:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][C:52]([F:55])([F:54])[F:53])[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: FC(F)(F)Oc1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3OC(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-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 1-(bromomethyl)-2-(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS (m/e): 457.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]([NH2:30])=[O:29])[C:16]([C:31]([F:34])([F:33])[F:32])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH2:35]=O>CO>[CH3:35][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]([NH2:30])=[O:29])[C:16]([C:31]([F:33])([F:32])[F:34])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Reactant: C=O
Solvent: CO
Product: CN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
NaHB(OAc)3 (147 mg, 0.693 mmol) was added cautiously to a stirred solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (35) (82 mg, 0.17 mmol) in 37% aqueous formaldehyde solution (39 μL, 0.52 mmol) and MeOH (5.0 mL). The reaction mixture was stirred for 1 hr and then quenched with water (50 mL). The resultant precipitate was removed by filtration, washed with cyclohexane and dried under high vacuum to yield the title compound as a white solid (82 mg, 97%). LCMS-A: rt 4.751 min; m/z 488.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][N:29]1[C:38](=[O:39])[C:37]3[CH:40]=[CH:41][CH:42]=[C:35]4[C:36]=3[C:31](=[C:32]3[CH:46]=[CH:45][CH:44]=[CH:43][C:33]3=[CH:34]4)[C:30]1=[O:47])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2.[CH2:48]=O>C(O)C>[O:47]=[C:30]1[C:31]2[C:36]3[C:35](=[CH:42][CH:41]=[CH:40][C:37]=3[C:38](=[O:39])[N:29]1[CH2:28][CH2:27][N:26]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][N:3]3[C:4](=[O:19])[C:5]4[CH:18]=[CH:17][CH:16]=[C:7]5[C:6]=4[C:11](=[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]4=[CH:8]5)[C:2]3=[O:1])[CH2:48]1)[CH:34]=[C:33]1[CH:43]=[CH:44][CH:45]=[CH:46][C:32]1=2
Reactant: C=O
Reactant: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Solvent: CCO
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCN1CCCN(CCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)C1
Yield: 58 %

Procedure:
A mixture of 0.5 g (0.8 mmol) of N,N'-Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine and 1 ml of 36% formaldehyde in 100 ml of ethanol was refluxed for 7 hours. The solid was filtered, washed, dried, and recrystallized from toluene. 0.3 g (58%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]hexahydropyrimidine were obtained. M.p. 222° C. (toluene).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (95 mg, 0.43 mmol) in CH2Cl2/pyridine 9/1 (10 ml) was treated with 4-((S)-2-fluoro-1-methyl-ethyl)benzenesulfonyl chloride (132 mg, 0.55 mmol). Purification by flash column chromatography (CH2Cl2:MeOH, 97:3) gave the title compound (100 mg, 55% for step 31.4 and this step) as a gum.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:15](#[N:25])[CH2:16][C:17]1[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[C:15]([C:16]1([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:25]
Reactant: N#CCc1ccccc1C#N
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2C#N)CC1
Temperature: 25 °C

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (19 g, 78 mmol) and homophthalonitrile (8.6 g, 60 mmol) and cesium carbonate (79 g, 241 mmol) was stirred at 60° C. for 12 hours. The solution cooled to room temperature and diluted with 500 ml EtOAc and washed with saturated aqueous NaHSO4 and saturated aqueous NaCl. The solution was dried over Na2SO4, concentrated in vacuo, and purified by PCTLC (30% EtOAc in Hexane) to afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-cyanophenyl) piperidine as a yellow/orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]=1[O:17][CH3:18])[CH3:2].[Cl-:20].[Li+]>O1CCOCC1.[Cu](Cl)Cl>[Cl:20][CH:14]1[C:13](=[O:19])[C:12]([C:4]2[C:5]([CH2:10][CH3:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH2:1][CH3:2])=[C:16]([O:17][CH3:18])[CH2:15]1
Reactant: [Cl-]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC)CCC1=O
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CCc1cc(C)cc(CC)c1C1=C(OC)CC(Cl)C1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone (0.715 g, 2.77 mmol) in 1,4-dioxane (45 ml), and under an atmosphere of nitrogen, are added copper (II) chloride (0.743 g, 5.53 mmol) and lithium chloride (0.176 g, 4.15 mmol). The reaction is heated at reflux for 7 hours and allowed to cool to room temperature overnight. The remaining solid is removed by filtration and washed with ethyl acetate (50 ml). The filtrate is washed with water (2×25 ml) and the aqueous washings re-extracted with ethyl acetate (1.5 ml). The combined organic phases are washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give a brown oil. The crude product is purified by column chromatography on silica gel to give 5-chloro-2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:14][S:15]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To 1,1-dimethylethyl 1-piperazinecarboxylate (568 g, 3.05 mol) in DCM (4 L) was added TEA (617 g, 6.10 mol). After stirring for 10 min at 0° C., methanesulfonyl chloride (384 g, 3.35 mol) was added via addition funnel. The mixture was stirred at rt overnight. The mixture was poured into H2O (1 L) and extracted with DCM (1 L). The organic layer was separated, washed with H2O (1 L), dried (Na2SO4), and rotovapped down to provide the title compound of step A (720 g, 2.72 mol, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 2.76 (s, 3H), 3.11-3.17 (m, 4H), 3.50-3.53 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: Oc1cc(Nc2ncccn2)ccc1Cl
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ncccn2)ccc1Cl
Yield: 53 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-5-(pyrimidin-2-ylamino)phenol (30 mg, 0.14 mmol) and Cs2CO3 (47 mg, 0.14 mmol) in acetone (2.0 mL) was treated with 4-bromo-2-methyl-2-butene (16 μL, 0.14 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 53% yield (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[S:5][C:4]=1[C:16]([O:18]C)=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[C:8]([C:7]1[C:3]([O:2][CH3:1])=[C:4]([C:16]([NH:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH2:27][CH3:28])=[O:18])[S:5][C:6]=1[C:12]([O:14][CH3:15])=[O:13])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1OC
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1OC

Procedure:
The above compound was prepared from trimethyl 3-methoxy-2,4,5-thiophene tricarboxylate and (±) 2-(aminomethyl)-1-ethyl-pyrrolidine as in Example 5.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[C:2]#[CH:3].Br[C:10]1[C:11]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1.C(N(CC)CC)C>CN(C=O)C.O.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]1[C:11]2[N:12]=[C:13]([C:16]#[N:17])[N:14]=[CH:15][C:10]=2[CH:3]=[C:2]1[CH2:1][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: C#CCn1ccnc1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)Cn1c(Cn2ccnc2)cc2cnc(C#N)nc21
Temperature: 80 °C
Yield: 64 %

Procedure:
1-Prop-2-ynyl-1H-imidazole (15 mmol) is dissolved in DMF at room temperature under nitrogen atmosphere. To the solution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (8 mmol), triethylamine (24 mmol), copper(I) iodide (0.8 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.4 mmol) are added successively. The mixture is heated at 80° C. under nitrogen atmosphere for 3 h. After cooling at room temperature, the mixture is diluted with H2O and AcOEt and filtered with celite. The organic layer is taken, dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (AcOEt:MeOH=20:1) to give 7-(2,2-dimethyl-propyl)-6-imidazol-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 64% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(O)ccc1Br
Solvent: ClCCl
Product: COc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromo-3-methoxyphenol (2.0 g, 0.0098 mol), phenylboronic acid (3.0 g, 0.025 mol), TEA (8.2 mL, 0.059 mol), cupric acetate (2.9 g, 0.016 mol) and DCM (100 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.81 (s, 3H), 6.45 (dd, J=8.72, 2.65 Hz, 1H), 6.61 (d, J=2.53 Hz, 1H), 7.01 (d, J=8.34 Hz, 2H), 7.12 (t, J=7.33 Hz, 1H), 7.34 (t, J=7.96 Hz, 2H), 7.42 (d, J=8.59 Hz, 1H).