Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][NH2:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][NH:10][C:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]2)=[O:27])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1CN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
The mixture of (4,5-dichloro-2-methoxyphenyl)methanamine (0.8 g, 3.90 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.88 g, 3.84 mmol), BOP (2 g, 1.16 mmol) and DIEA (1.6 g, 2.91 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1) to afford the desired product (0.987 g, 62% yield). ESI-MS m/z: 415.4 [M−H]−.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])(=[O:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:38][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)n2)c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOH*H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (20 mg). MS found for C22H21N7O2 as (M+H)+ 416.3. λ=211.3, 250.9.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(O)CCC>[ClH:15].[NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[NH:28][C:27]2[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCCCO
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Nc3ccc(Cl)cc3)c2c1
Product: Cl

Procedure:
Under exclusion of air, 207 mg (0.66 mmol) 7-acetamino-1-chloro-4-(4-pyridylmethyl)-phthalazine is heated to boiling for 4 h in 2.7 ml 1-butanol with 253 mg (1.98 mmol) 4-chloroaniline. After cooling, the dark suspension is filtered off, washed with 1-butanol and ethanol, and dried to obtain title compound: m.p.: 260-265° C.; HPLC: tRet(GradS40)=10.9; FAB MS (M+H)+=404.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)=[S:25]
Reactant: S=C=S
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(CSC(=S)N2[C@H](CO)Cc3c([nH]c4ccccc34)[C@@H]2C)cc1

Procedure:
In the same manner as described in Example 34 by using (1RS, 3RS)-cis-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (2.16 g), triethylamine (1.4 ml), CS2 (0.60 ml), 4-methoxybenzyl chloride (2.01 g) and dimethylsulfoxide (10 ml), there is prepared the title compound (3.0 g, 73%) as colorless needles, m.p. 152°-153° C. (recrystallized from aqueous ethanol), NMR (CDCl3, δ): 3.79 (s, 3H, ##STR21## 4.57 (s, 2H, ##STR22## Mass m/e: 412 (M+), 258 (M+ -- ##STR23##
Reaction SMILES: CC1C=CC(S([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I-:25].[Na+].CC(C)=O>C1CCCCC1>[I:25][CH2:11][C@H:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2Cc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of (S)-5-[[(4-methylphenyl)sulfonyl]methyl]-1-(phenylmethyl)-2-pyrrolidinone (244.5 g, 0.68 mol), sodium iodide (305 g, 2.03 mol), and 3 L of acetone was refluxed and stirred overnight. The suspension was cooled to 10° C. and was filtered. The salts were rinsed with three 250-mL portions of acetone, and the acetone washes and filtrate were concentrated on a rotary evaporator to a thick slurry. Methylene chloride (1.5 L) was added and the white precipitate was filtered off and washed with methylene chloride. The filtrate was dried over magnesium sulfate (MgSO4), filtered through a pad of silica gel, and concentrated on a rotary evaporator to give 196.8 g (92% yield) of (S)-5-iodomethyl-1-(phenylmethyl)-2-pyrrolidinone as an off-white solid, mp 92°-94° C. (cyclohexane). 1 h NMR (CDCl3) δ 1.7-2.75 (m, 4 H, CH2), 3.18-3.28 (m, 2 H, CH2I), 3.42 (m, 1 H, NCH), 3.98 and 4.05 (AB, 2 H, Jgem =15 Hz, CH2Ph), 7.20 (m, 5 H, phenyl). [α]25D =+12.11 (c 0.35, methanol). Anal. Calcd for C12H14NOI: C, 45.73; H, 4.48; N, 4.44. Found: C, 45.58; H, 4.35; N, 4.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Cl:25][S:26](O)(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(O)Cl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1.70 g (5.21 mmol) of 2-(2-ethoxy-phenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are added slowly to 3.12 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 2.10 g (94%) of a colourless foam.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])C1=O.[CH2:14](O)[CH2:15][CH2:16][CH3:17].[OH:19]O>CN(C)C=O>[C:6]([O:7][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:3]
Reactant: CCCCO
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 56 %

Procedure:
8.6 parts of 50 percent strength by weight sodium hydride are added to 14.7 parts of isatin in 250 parts of n-butanol and 100 parts of dimethylformamide at 25° C. After one hour, 8 parts of 50 percent strength by weight hydrogen peroxide solution are slowly added to the violet solution, and the temperature is allowed to rise to 50° C. The mixture is then stirred for one hour and is worked up as described in Example 1. 10.8 parts (56% of theory) of n-butyl anthranilate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[N:15][O:16][C:17]=1[CH3:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1noc(C)c1N
Solvent: c1ccncc1
Product: Cc1noc(C)c1NS(=O)(=O)c1ccc(Br)cc1
Yield: 86.6 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (4.56 g, 17.9 mmol) and 4-amino-3,5-dimethylisoxazole (2.02 g, 18.0 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.15 g, 15.5 mmol, 87%). 5H (CDCl3, 300K) 7.69 (2H, dd, J=6.9 Hz 1.7 Hz), 7.65 (2H, dd, J=6.9 Hz 1.7 Hz), 6.11 (1H, s), 2.12 (3H, s), 1.91 (3H, s). m/z (ES+, 70V) 333.0 (MH+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C(Cl)(=O)C.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12]>>[CH2:1]([O:4][C:10]([C@@H:11]([C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])=[O:9])[CH2:2][CH3:3]
Reactant: CCCO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Solvent: CC(=O)Cl
Product: CCCOC(=O)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37.5 °C
Reaction time: 2.5 h
Yield: 73.4 %

Procedure:
3.917 kg (65 mol) of 1-propanol was placed in a reactor, and the temperature within the reactor was lowered to a temperature between −10° C. to 10° C. Then, 0.523 kg (6.7 mol) of acetyl chloride was added slowly thereto at a temperature between −10° C. to 35° C. To the solution, 1 kg (6.7 mol) of L-arabinose was added, and the mixture was warmed to 35-40° C. and stirred at that temperature for 2-3 hours, and then at 27-32° C. for 20 hours. After completion of the reaction, the solids were filtered and washed with 0.536 kg of 1-propanol. The filtered solids and 3.6 liters of dichloromethane were placed in a reactor and stirred for 1-2 hours. After this, 0.079 kg of pyridine was added thereto, and the mixture was stirred for 30 minutes, filtered, washed with 0.662 liters of dichloromethane, and then dried in a vacuum, thus obtaining 1.024 kg (80% yield) of 1-propoxy-L-arabinose. 1H NMR (D2O): δ 4.85 (d, 1H), 3.90 (m, 1H), 3.85-3.65 (m, 3H), 3.55 (m, 2H), 3.40 (m, 1H), 1.55 (m, 2H), 0.85 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccn3)C3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2-hydroxypyridine (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). White solid (79%). MS (Turbo Spray): m/z=468.3 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].[CH3:10][N:11]1[C:19]2[N:18]=[CH:17][N:16]([CH3:20])[C:15]=2[C:14](=[O:21])[NH:13][C:12]1=[O:22].O>CS(C)=O>[CH2:2]([N:13]1[C:14](=[O:21])[C:15]2[N:16]([CH3:20])[CH:17]=[N:18][C:19]=2[N:11]([CH3:10])[C:12]1=[O:22])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.2 %

Procedure:
1-(5,6-Oxidohexyl)-3,7-dimethylxanthine was synthesized and used as an intermediate for synthesizing inventive compounds nos. 1517 and 1595 as described in examples 2 and 3 below. A mixture of l-bromo-5-hexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and 3,7-dimethylxanthine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hr. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (17 g, 98% yield) as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]([Cl:37])=[C:15]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH:29]4[CH2:31][CH2:30]4)[C:25]4=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]4[N:23]=3)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=2)[CH2:9][C@H:8]1[O:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:37][C:14]1[C:15]([NH:21][C:22]2[N:27]=[C:26]([NH:28][CH:29]3[CH2:30][CH2:31]3)[C:25]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]3[N:23]=2)=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][C@@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:8]([O:38][Si:39]([CH:43]([CH3:45])[CH3:44])([CH:46]([CH3:48])[CH3:47])[CH:40]([CH3:41])[CH3:42])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (7.5 μl, 0.10 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.040 mmol) and triethylamine (17 μl, 0.120 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 0-40% ethyl acetate/dichloromethane). N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)methanesulfonamide (28 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:15].[C-:16]#[N:17].[K+]>>[NH2:15][C:10]1([C:16]#[N:17])[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Product: N#CC1(N)CCN(Cc2ccccc2)C1

Procedure:
According to a particular variant of embodiment of this synthesis process, 1-benzyl-3-pyrrolidinone is treated with an ammoniacal solution of ammonium chloride and of potassium cyanide to obtain (±)-3-amino-1-benzyl-3-cyanopyrrolidine. This compound is then converted by acid or basic hydrolysis to (±)-3-amino-1-benzyl-3-pyrrolidinecarboxylic acid, and lastly a reduction with hydrogen, preferably a catalytic hydrogenolysis, is carried out to obtain (±)-3-amino-3-pyrrolidinecarboxylic acid or (±)-cucurbitine.
Reaction SMILES: CI.[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:36][N:5]1[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[C:4]1=[O:3]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
Methyl iodide (2 M in tert-butyl methyl ether, 63 μL, 0.13 mmol) is added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6, 50 mg, 0.11 mmol) and cesium carbonate (68 mg, 0.21 mmol) in N,N-dimethylformamide (2.0 mL), and the mixture is stirred at room temperature over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 39 mg; ESI mass spectrum [M+H]+=491; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:18].CO>CO>[ClH:18].[NH2:10][CH:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCC(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (1-acetylpiperidin-4-yl)carbamate (330 g, 1.36 mol) in MeOH (1000 mL) was added HCl/MeOH (4M, 300 mL) over 30 min to maintain the temperature at 0° C. After addition, the mixture was stirred at 0° C. for another 2 h and then concentrated to give the crude product. Two batches were run in parallel and produced a combined crude product weight of 310 g. This crude was used in next step without further purification. 1H NMR (400 MHz, D2O) δ 4.35 (dd, J=2.0, 12.0 Hz, 1H), 3.98-3.85 (m, 1H), 3.44-3.30 (m, 1H), 3.18-3.05 (m, 1H), 2.75-2.58 (m, 1H), 2.06-1.92 (m, 5H), 1.61-1.31 (m, 2H); LCMS (m/z): 143.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-])=O.C(N(C(C)C)CC)(C)C>CC(O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccc(O)cc3)ncn2)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4-Chloro-6-(4nitro-phenoxy)pyrimidine (Stage 22.5; 3 g, 11.9 mmol), 4-nitrophenol (1.95 g, 17.9 mmol), and diisopropylethylamine (DIPEA) (3.04 ml, 179 mmol) dissolved in 2-propanol (50 ml) are stirred at 85° C. for 18 h. After concentrating the reaction mixture under reduced pressure, the product precipitates as a colorless fine solid: M+H=245.0; 1H-NMR (400 MHz, DMSO-d6): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5 Hz, 2H, phenyl-NO2), 8.26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H, phenyl-NO2), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H, phenyl-OH), 6.15 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=2:1): 0.48.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OC)[CH2:21][CH2:22][CH2:23]Cl)#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:17]([N:19]=[C:20]1[CH2:21][CH2:22][CH2:23][N:1]1[C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:18]
Reactant: COC(CCCCl)=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=NC#N)[C@@H]1O
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A solution of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (5.0 g), methyl N-cyano-4-chlorobutyrimidate (7.36 g), triethylamine (4.8 ml), and toluene (12 ml) was stirred at 100° C. for 2 days. After being cooled to room temperature, the reaction mixture was concentrated. The residue was taken up in ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, and concentrated. After purification by column chromatography on silica gel (elution with chloroform-methanol 25:1), the crude product was further purified by recrystallization from ethyl acetate to give trans-4-(2-cyanoiminopyrrolidin-1-yl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (0.87 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[S:35]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:40][C:37]4[CH:38]=[CH:39][S:35][CH:36]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCc1ccsc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccsc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
Diethyl azodicarboxylate (197 μl, 1.2 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 24), 3-thiophenemethanol (107 mg, 0.93 mmol) and triphenylphosphine (328 mg, 1.2 mmol) in methylene chloride (6 ml) cooled at 0° C. The mixture was stirred for 2 hours at ambient temperature and further triphenylphosphine (157 mg, 0.57 mmol), 3-thiophenemethanol (107 mg, 0.93 mmol) and diethyl azodicarboxylate (98.5 μl , 0.59 mmol) were added. The mixture was stirred for 2 hours at ambient temperature and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (4/6). The resulting oil was dissolved in ether and a 5M solution of hydrogen chloride in isopropanol (1 ml) was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline hydrochloride (59 mg, 20%). 1H NMR Spectrum: (DMSOd6) 3.99(s, 3H); 5.34(s, 2H); 7.25(d, 1H); 7.43(d, 1H); 7.45(s, 1H); 7.58-7.63(m, 2H); 7.7(dd, 1H); 7.72(dd, 1H); 8.17(s, 1H); 8.78(s, 1H) MS-ESI: 416 [MH]+
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].C[CH:18]([CH3:25])[C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[O:20].[CH3:26]COCC>CO>[OH:1][CH:2]([CH2:16][NH:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:25][CH3:26])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1ccccc1OCC1CO1
Reactant: CC(C)C(=O)NCCN
Reactant: CCOCC
Solvent: CO
Product: CCCC(=O)NCCNCC(O)COc1ccccc1CC(=O)OC
Yield: 9 %

Procedure:
A mixture of 5.0 g (0.02 mole) of methyl 2-(2,3-epoxypropoxy)-phenylacetate and 2.93 g (0.02 mole) of 2-(2-methylpropionamido)ethylamine in 200 ml of methanol, was heated to reflux for 4 hr. The mixture was concentrated under reduced pressure to afford a dark brown oil which was then stirred with 100 ml of ether for 15 min. to yield an off-white solid. The product was collected by filtration, washed with ether and recrystallized three times from ethyl acetate to provide 0.7 g (9%) of white crystals, which melted at 109°-111° C. The IR and NMR spectra and elemental analysis were consistent with the assigned structure.