Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:8]2[CH:18]=[CH:17][CH:11]=[CH:10][C:9]=2[C:1]([OH:2])=[O:4])=[CH:18][CH:17]=1)=[O:13])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Cu]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 145.5 %

Procedure:
Potassium carbonate (14 g) was added to a solution of 2-indobenzoic acid (50 g) in nitrobenzene (50 ml) at 140°-150° C. with stirring. The mixture was stirred for an additional 10 minutes after the addition. Then, ethyl 4-hydroxybenzoate (33.5 g), potassium carbonate (28 g) and copper (3 g) were added. The mixture was stirred at 150°-160° C. for 30 minutes and allowed to cool. After the addition of water, the mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallized from dilute ethanol to give the title compound (42 g, 72%), m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[CH:31]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:36][NH:37][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:28])([F:29])[F:1])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCC1CCCC1
Agent: Cl
Product: O=C(NCC1CCCC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 69 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) were reacted with C-cyclopentylmethylamine, hydrochloride analogously to example 3d. Yield: 69%, M+H+: 485.28.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[CH2:1]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=2)[CH2:14][CH:13]([OH:15])[CH2:11]1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: ClCC1CO1
Product: CCN1CC(O)Cc2ccc(C)cc21
Reaction time: 72 h

Procedure:
N-ethyl-m-toluidine (1.0 mole) and epichlorohydrin (225 g) were mixed and allowed to stand three days at room temperature. The reaction mixture was heated at 140°-145° C. for 6 hrs. and then distilled under vacuum. The product (100 g) which boiled at 143° C. at 1.1 mmHg was recovered in 52% of the theoretical yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[C:12]1([CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccccc1)c1ccncc1
Yield: 78.7 %

Procedure:
Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78%) was obtained as a crystalline solid: m. p. 101–103° C. Anal. Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[CH:6][N:5]=[C:4]([CH:16]=O)[CH:3]=1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22](/[N:24]=[CH:16]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[CH:6][N:5]=1)=[O:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCC(F)(F)C(F)F
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)C(F)F
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.38 g, pale yellow solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde (1.20 g, 4.79 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (872 mg, 7.19 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: I[CH2:2][CH:3]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[C:3]1([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: ICC1Cc2ccccc21
Reactant: O=C(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(CC2=Cc3ccccc32)CC1
Reaction time: 6 h

Procedure:
0.028 mole of 1-(iodomethyl)benzocyclobutene (Process 1, stage G), 0.028 mole of 4-piperidinecarboxylic acid and 0.028 mole of triethylamine are mixed in 95 ml of dimethylformamide. The mixture is brought to 60° C. for 6 hours. It is evaporated to dryness, the residue is taken up with ethyl acetate and water and settling is allowed to take place.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:10]([NH2:12])[CH3:11].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:10]([NH:12][C:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:31][CH:30]=1)[C:34]([CH3:46])=[C:35]2[CH3:45])=[O:43])[CH3:11]
Reactant: C[C@H](N)c1cccc(F)c1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,3-difluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 539 [M+H]+.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1ccccc1O
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccccc1OC)c1ccccc1

Procedure:
A mixture of 130 g (1.05 m) guaiacol, 243 g (1 M) ethyl α-bromophenylacetate, 150 g of potassium carbonate and 1.5 L of acetone was refluxed for 96 hours, cooled and filtered. The solvent was removed at reduced pressure and the residue dissolved in toluene. After washing with dilute sodium hydroxide, then water, the solvent was removed and the residue distilled. The fraction boiling at 158-163°/0.4 mm was collected, weight 263 g.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=O>>[CH3:29][O:28][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:9]1[CH2:10][CH2:5][CH:30]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:7][CH2:8]1)[N:9]=[CH:8][C:7]([C:12]#[N:13])=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.39 mmol) of 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)-phenylamino]-quinoline-3-carbonitrile and 299 mg (1.94 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 120 mg of 6-methoxy-4-[4-(pyridin-3-yloxy) phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[N:20]1([C:25]2[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][C:26]=2[CH:27]=O)[CH:24]=[N:23][CH:22]=[N:21]1.N1CCC[C@H]1C(O)=O>CO>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:30]([CH:33]=[CH2:34])[CH:31]=[CH:32][C:25]=1[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: C=Cc1ccc(-n2cncn2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: C=Cc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 60 °C
Yield: 8.8 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in MeOH (5 mL) are added crude 2-1,2,4-triazol-1-yl-5-vinyl-benzaldehyde (93 mg, 0.47 mmol) and L-proline (4 mg, 0.04 mmol) at room temperature. The solution is heated to 60° C. for 12 hours, then cooled down and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (15 mg, 9%) as a white solid. LCMS (ESMS): m/z 437.72 (M++1)
Reaction SMILES: O[C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:17]1CCCC1>>[OH:17][C:3]1([CH2:8][OH:10])[N:4]=[CH:5][CH:6]=[N:7][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(O)c1nccnc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1(O)CN=CC=N1

Procedure:
3-Hydroxypyrazine-2-carboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-hydroxy-3-hydroxymethylpyrazine. Treatment of 3-hydroxy-2-hydroxymethylpyrazine at room temperature with thionyl chloride gives 3-hydroxy-2-hydroxy-2chloromethylpyrazine and reacting this intermediate with cysteamine by the procedure of Example 62 gives 2-[(2-aminoethyl)thiomethyl]-3-hydroxypyrazine.
Reaction SMILES: C[S:2]([NH:5][C:6]([C:8]1[CH:47]=[CH:46][C:11]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:16]([CH2:25][N:26]([C@@H:34]([C:36]3C4C(=CC=CC=4)[CH:39]=[CH:38][CH:37]=3)[CH3:35])C(=O)OC(C)(C)C)[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3].Cl.[O:49]1[CH2:54]COCC1>O1CCOCC1>[CH3:54][O:49][S:2]([NH:5][C:6](=[O:7])[C:8]1[CH:47]=[CH:46][C:11]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:16]([CH2:25][NH:26][C@@H:34]([C:36]3[C:47]4[C:8](=[CH:9][CH:10]=[CH:11][CH:46]=4)[CH:39]=[CH:38][CH:37]=3)[CH3:35])[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)(=[O:3])=[O:4]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(C(=O)NS(C)(=O)=O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: COS(=O)(=O)NC(=O)c1ccc(C(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 1.6 ml 1,4-dioxane solution of 160 mg of tert-butyl {[(3R,4S)-1-(4-{[(methylsulfonyl)amino]carbonyl}benzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 1.5 ml of 4 M hydrogen chloride/1,4-dioxane and stirred at room temperature for 4Hours. The reaction solution was concentrated under a reduced pressure and dissolved in water. This was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was crystallized with ethyl acetate to obtain 85 mg of N-(methoxysulfonyl)-4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}benzamide as colorless crystals.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: O=C(Cl)Oc1ccccc1Cl
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1

Procedure:
2-(chloro)phenyl chloroformate (5.00 g, 26.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.50 g, 20.2 mmol) according to general procedure 1. Yield=4.56 g, 82%. m/z MH+=278.13. HPLC rt=9.3 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:39][C:40](=[O:42])[CH3:41])[CH:31]=[CH:32][C:33](Cl)=[O:34])(=[O:26])[CH3:25].Cl>CN(C)C=O>[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:39][C:40](=[O:42])[CH3:41])[CH:31]=[CH:32][C:33]([NH:13][C:12]1[CH:14]=[C:15]([CH3:16])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:17])[CH:11]=1)=[O:34])(=[O:26])[CH3:25]
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1OC(C)=O
Reactant: Cc1cc(N)cc(C)c1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C=CC(=O)Nc2cc(C)c(OCc3ccccc3)c(C)c2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 1.6 g of 4-benzyloxy-3,5-dimethylaniline in 30 ml of dimethylformamide is added under ice-cooling 1.17 g of potassium carbonate, and then a solution of 2.0 g of 3,4-diacetoxycinnamoyl chloride in 10 ml of dimethylformamide is added dropwise at 5° to 7° C., followed by stirring at room temperature for 2 hours. The reaction mixture is poured into ice-water, adjusted to pH 1 with 10 % hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and then concentrated. Recrytallization of the residue from methanol gives 2.64 g of N-(3,4-diacetoxycinnamoyl)-4-benzyloxy-3,5-dimethylaniline.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[NH:20][C:21]([NH:23][C:24]([O:26][CH3:27])=[O:25])=[S:22].[OH-].[Na+].[CH3:30]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]1[NH:20][C:21](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:22][CH3:30]
Reactant: CCCSC1(C)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCSC1(C)C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a suspension of 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.02 g; 0.01 mole) in acetone (60 ml) and water (20 ml) there is added 50% aqueous sodium hydroxide (0.8 g; 0.01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; 0.01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is air dried to afford 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxy-S-methyl isothioureido)-4-propylthiobenzene (3.6 g; 86.6%), m.p. 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:20])[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccc(OC)cc2)nn3C2CCCCO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.9 %

Procedure:
To a solution of methyl 4-{N-[3-(4-methoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazol-5-yl]carbamoyl}benzoate (0.099 g, 0.20 mmol) in anhydrous tetrahydrofuran (5 mL), 6.0N aqueous HCl was added (5 mL). The solution was stirred at room temperature for 48 hours. The reaction mixture was then neutralized with saturated aqueous sodium bicarbonate and the organic layer was extracted with ethyl acetate (10 mL, 3 times). The organic layer was dried over Na2SO4 and evaporated to dryness to afford the title compound (0.081 g, quantitative yield): ES-MS (m/z) 402 [M+1]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[I:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[I:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: BrCc1cccc(I)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1cccc(I)c1
Yield: 90.8 %

Procedure:
A mixture of potassium cyanide (4 g) and tetra-n-butylammonium bromide (0.32 g) in water (20 ml) was added to a solution of 3-iodobenzyl bromide (5.92 g) in methylene chloride (20 ml) and the mixture was heated to reflux for 2 hours. The organic phase was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent to give 3-iodophenylacetonitrile (4.4 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:12]([CH3:27])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH2:17][C@H:15]([OH:16])[C@H:14]([CH3:18])[C@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C@@H:12]([CH3:27])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1[C@H]2O[C@H]2C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
Compound α37 (39 mg, 0.095 mmol) was dissolved in dry toluene (1.0 mL), and the temperature lowered to −78° C. To this cold solution was added THF (10 μL, 0.12 mmol), followed by DIBAL-H solution (0.20 mL of 1.55M in toluene) under nitrogen, and the reaction stirred magnetically at −78° C. for 3 hours. Upon completion, the reaction was quenched by 5% HCl aqueous solution, and extracted with ethyl acetate (3×5 mL). The organic layers were combined and washed with brine, and dried over anhydrous Na2SO4. The crude reaction mixture was purified by flash column chromatography (ethyl acetate/hexanes; 1:3) to afford 34 mg (85%) of a mixture (1,2 vs 1,4-reduction; 4.5:1). 13 mg (35%) of pure 60 was obtained via flash column chromatography eluting with CH2Cl2: CH3CN (25:1). [α]20D=−77.7 (c=0.65, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.87-7.91 (m, 2H), 7.49-7.63 (m, 3H), 7.31 (br d, J=8.4 Hz, 1H), 3.80 (d, J=5.1 Hz, 1H), 3.66 (m, 1H), 3.32 (d, J=9.3 Hz, 1H), 2.94 (m, 2H), 2.57 (dt, J=16.5 Hz, 2.1 Hz, 1H), 1.98 (m, 1H), 1.18 (d, J=7.2 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H), 0.88 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C NMR (C6D6, 75 MHz) δ 143.1, 140.4, 138.9, 133.5, 129.1, 128.8, 79.6, 71.0, 39.6, 38.0, 34.4, 25.9, 18.2, 18.0, 15.0, −4.4, −4.8; LRMS (CI): m/z 411 [M+H]+; HRMS (CI) calculated for C21H35O4SSi, 411.2025; found, 411.2025
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:27]=[C:25]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:9][C:10]=3[C:11]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)(C)C)cc12)C(=O)OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NC(=O)C(C)(C)C)ccc3ncn2c1=O
Temperature: 260 °C
Yield: 81.4 %

Procedure:
A mixture of dimethyl [{6-pivalamido-4-quinazolinylamino}methylene]propanedioate (24.5 g) and diphenyl ether (150 ml) was heated at 260° C. for 20 minutes and cooled to ambient temperature. To the reaction mixture was added hexane to give crystals, which were filtered off, washed with hexane and dissolved in chloroform (400 ml) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to 200 ml and allowed to stand under cooling. The precipitated crystals were filtered off and washed with chloroform to give crystalline methyl 4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (18.29 g). The mother liquor was concentrated under reduced pressure to give crystals, which are purified by a column chromatography on silica gel (50 g) (Developing solvent: 5% methanol-chloroform solution) and recrystallized from chloroform to give the same object compound (3.2 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[F:5][C:6]([F:21])([S:17](F)(=[O:19])=[O:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]>C(OCC)(=O)C>[CH2:1]([NH:4][S:17]([C:6]([F:5])([F:21])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])(=[O:19])=[O:18])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
n-Propylamine (26.60 g) and ethyl acetate (120 mL) were placed in a glass flask equipped with a stirrer, a condenser and a thermometer, and perfluorobutansulfonyl fluoride (available from Azumax Company) (45.31 g) was added dropwise over 1 hour using a dropping funnel to the flask in an ice bath. After completion of the dropping, the mixture in the flask was heated at 40□ with an oil bath and the mixture was stirred for 5 hours. Then the mixture was cooled to the room temperature and was washed twice with 75 ml of 9% aq. hydrochloric acid solution. Ethyl acetate layer was dried with magnesium sulfate and then was filtered off. Ethyl acetate was evaporated under vacuum to obtain N-propylperfluorobutanesulfonamide (46.8 g).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]3[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]3[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:34][CH3:35])=[O:21])=[CH:16][CH:15]=3)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCO
Reactant: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Reaction time: 72 h

Procedure:
A suspension of (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3,-dipropyl-9H-purin-8-yl)cinnamic acid (4.00 g, 10.4mmol) (Example 6) and concentrated sulfuric acid (1 ml) in absolute ethanol (1.5 L) was refluxed for 2 hours with slow distillation of 75 ml of vapor. Reflux was continued for 3 days with exclusion of moisture with 50 ml distillate being removed during the final 4 hours. The cooled suspension was filtered to yield ethyl (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purin-8-yl)cinnamate as a pale yellow solid. mp >300° C. Analysis for (C22H26N4O4). C,64.38; H,6.38; N,13.65. Found: C, 64.34; H, 6.43; N, 13.63.