Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[F:10][B-:11]([F:14])([F:13])[F:12].[C:15]1([C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O+]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.C(OCC)C>ClCCl>[F:10][B-:11]([F:14])([F:13])[F:12].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N+:5]1[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:24][C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:26][C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1Cl
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccccc1C[n+]1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
2-Chlorobenzylamine (2.0 g, 14 mmol) was added dropwise to a suspension of 2,4,6-triphenylpyrylium tetrafluoroborate (5.1 g, 13 mmol) in dichloromethane (40 mL). The reaction mixture was stirred for 16 h. Ethanol (4 mL) and excess diethyl ether were added to precipitate the product. The precipitate was filtered and dried. This provided 6.14 g (92%) of N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate.
Reaction SMILES: C=CCCCCCC.[C:9]([OH:24])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCCCC.OO>C1(C)C=CC=CC=1>[CH2:9]1[O:24][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: OO
Solvent: C=CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC1CO1
Yield: 35 %

Procedure:
A mechanically stirred suspension of immobilized C. antarctica lipase (100 mg, according to example 1) in toluene (13.5 ml), 1-octene (1.5 ml, 9.54 mmol) and myristic acid (0.22 g, 0.95 mmol) was heated to 50° C. To this mixture hydrogen peroxide (0.8 ml, 60% (w/v)) was added in four equal portions after 0, 1.5, 3 and 4.5 hours (14 mmol in all). After 24 hours 35% octene oxide was formed as determined by gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([C:29]([F:32])([F:31])[F:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:22]([C:29]([F:32])([F:30])[F:31])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(N=C=S)c(C(F)(F)F)n1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)nc2C(F)(F)F)c1NCCCO
Yield: 96.9 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol) and 3-isothiocyanato-6-methoxy-2-(trifluoromethyl)pyridine (1.81 g, 7.73 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give the title compound (1.85 g, 3.75 mmol, 97%) as a pale red amorphous.
Reaction SMILES: C(=N[N:9]=[C:10](Cl)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)C1C=CC=CC=1.[C:22]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)(=[S:24])[NH2:23]>CO>[F:18][C:17]([F:19])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:10]2[S:24][C:22]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)=[N:23][N:9]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(C(Cl)=NN=Cc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of N-benzylidene-4-trifluoromethylbenzenecarbohydrazonoyl chloride (1.55 g), methyl 4-thiocarbamoylbenzoate (0.976 g) and methanol (50 ml) was stirred at 50° C. for 2 hrs. After cooling, the crystals were collected by filtration to give methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl]benzoate (1.03 g, yield 57%) as a colorless crystalline powder. melting point: 218–219° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[N:3]=1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>C(O)C>[N:10]1[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[C:8]([C:4]2[N:3]=[C:2]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[CH:7]=[CH:6][N:5]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1ccnc(-c2cnn3ccccc23)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 33, 130 mg, 0.56 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (326 mg, 1.63 mmol) in ethanol (5 mL) was heated overnight at 100° C. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was taken up in a mixture of chloroform and water. The aqueous layer was separated and washed with chloroform (×2). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (dichloromethane to 95:5 dichloromethane/methanol) to give the title compound (150 mg, 68%).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)=[O:6].C=O.[C:30]([BH3-])#N.[Na+]>C(O)(=O)C>[OH:1][CH:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:30])[CH2:11][CH2:10]2)=[O:6]
Reactant: [BH3-]C#N
Reactant: COc1cc(C(O)CNC(=O)c2ccc3[nH]ccc3c2)cc(OC)c1OC
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(O)CNC(=O)c2ccc3c(c2)CCN3C)cc(OC)c1OC
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A suspension of indole-5-carboxylic acid, (N-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]) amide (207 mg, 0.56 mmol) and paraformaldehyde (168 mg, 5.6 mmol) in acetic acid (5 mL) was treated with sodium cyanoborohydride (176 mg, 2.79 mmol), stirred for 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate and 10% NaHCO3, washed sequentially with 10% NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 218 mg of the desired product. MS (ESI(+)) m/z 387 (M+H)+;
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[N:22]1[CH:27]=[CH:26][C:25](=O)[CH2:24][CH:23]=1>COCCOC>[N:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:23]=1
Reactant: O=C1C=CN=CC1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccncc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-pyridone, using dry DME as reaction solvent: 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=5.0, 1.3 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.7, 2.6 Hz, 1H), 6.77 (dd, J=4.9, 1.3 Hz, 2H), 4.27 (t, J=5.2 Hz, 2H), 4.19 (q, J=8.5 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1.[OH-].[K+]>C(O)CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(OC)cc(Br)c3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1cc(Br)c2oc(C3CCNCC3)cc2c1
Reaction time: 18 h

Procedure:
7.6 g of 4-(7-bromo-5-methoxy-benzofuran-2-yl)-1-ethoxycarbonyl-piperidine are dissolved in 80 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the resulting cloudy solution is heated at 160° with vigorous stirring for 18 hours. The reaction mixture is cooled to 100°, diluted with 80 ml of toluene, and cooled further to 20°. The reaction solution is extracted twice with 1000 ml of water each time and then four times with 200 ml of a 10% solution of methanesulfonic acid in water each time. The resulting solution in methanesulfonic acid is adjusted to pH 12 by the addition of 30% sodium hydroxide solution and extracted by shaking with 1000 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and concentrated by evaporation. Crystallisation from ethyl acetate yields 4-(7-bromo-5-methoxybenzofuran-2-yl)-piperidine having a melting point of 149°-152°. There is obtained from the base by treatment with methanolic hydrochloric acid and recrystallisation from methanol/ether 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidine-hydrochloride having a melting point of 242°-243°.
Reaction SMILES: [CH:1]1[C:5]2[C:6](Cl)=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].Cl>C(O)(C)(C)C.CO>[CH3:20][O:19][C:17]([C:13]1[S:14][CH:15]=[CH:16][C:12]=1[NH:11][C:6]1[C:5]2[CH:1]=[CH:2][NH:3][C:4]=2[N:9]=[CH:8][N:7]=1)=[O:18]
Reactant: COC(=O)c1sccc1N
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 67.2 %

Procedure:
A suspension of 6-chloro-7-deazapurine (750 mg; 4.88 mmol), methyl 3-amino-2-thiophenecarboxylate (1.15 g; 7.33 mmol) and concentrated hydrochloric acid (410 μL; 4.9 mmol) in tert-butanol (15 mL) was microwaved at 75° C. for 3 h. The reaction mixture was diluted with methanol (15 mL) and filtered. The aqua solid was washed with methanol and dried under vacuo to afford the hydrochloric salt of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (900 mg, 59%) as a green-gray solid (HPLC: 99%, RT: 6.50 min). 1H NMR (DMSO-d6) 12.47 (br s, 1H), 10.68 (br s, 1H), 8.44 (s, 1H), 8.08 (br s, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.47 (dd, J=3.3, 2.2 Hz, 1H), 6.66 (br s, 1H), 3.83 (s, 3H); MS (m/z) 275 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-bromo-2-fluoro-benzoic acid (10.0 g, 45.7 mmol) in anhydrous dichloromethane (200 mL) was added oxalyl chloride (5.2 mL, 59.4 mmol) followed by addition of anhydrous DMF (0.2 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to dryness in vacuo to give title compound in quantitative yield, which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O.ClCCl>O1CCCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[O:9])[CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(Nc1ccc(F)cc1)NC1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)NC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of N-(piperidin-4-yl)-N′-(4-fluorophenyl)urea (0.3 g) in tetrahydrofuran (4 ml) were added in turn N,N-dimethylaminopyridine (0.23 g) and 4-fluorobenzenesulfonyl chloride (0.25 g) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N-(1-(4-fluorophenylsulfonyl)-piperidin-4-yl)-N′-(4-fluorophenyl)urea (0.468 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C:26]4(O)[C@H:31]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C@@H:30]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C@H:29]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[C@@H:28]([CH2:56][O:57][CH2:58][C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[O:27]4)[CH:22]=[CH:23][C:24]=3[Br:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:26]4[C@H:31]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C@@H:30]([O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C@H:29]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C@@H:28]([CH2:56][O:57][CH2:58][C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[O:27]4)[CH:22]=[CH:23][C:24]=3[Br:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: Brc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a stirred solution of (3R,4S,5R,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-bromo-phenyl]-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-ol (1.60 g, 1.72 mmol) in acetonitrile-dichloromethane mixture (3:1 mixture, 7 mL) was added triethylsilane (0.82 mL, 5.15 mmol) followed by boron trifluoride diethyletharate complex (0.42 mL, 3.43 mmol) at −30° C. After stirring for 2 h at 0° C., the reaction was quenched with aq. sodium bicarbonate (4 mL). The volatiles were evaporated under reduced pressure, and the resulting mixture was extracted with dichloromethane (2×20 mL). The organic layers were combined and washed with brine (3 mL), dried over sodium sulfate, then concentrated to a residue which was purified by column chromatography to furnish 4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine (1.10 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1>>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1cnccn1
Reactant: NCCN
Product: NCCNCc1cnccn1

Procedure:
Ethylenediamine is reacted with 2-chloromethylpyrazine by the procedure of Example 34 to give N-(2-pyrazinylmethyl)ethylenediamine. Heating the compound with S-methylisothiourea in water under reflux for 3 hours by the procedure of Example 1 gives 2-(2-pyrazinylmethylamino)ethylguanidine.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[C:29]3[N:28]=[CH:27][N:26]=[C:16]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]=3[N:14]=[CH:13]2)[C@@H:6]1[OH:30])[CH:2]=[CH2:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C.[Si:52](Cl)([C:65]([CH3:68])([CH3:67])[CH3:66])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:52]([C:65]([CH3:68])([CH3:67])[CH3:66])([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[O:8][C@@H:7]([N:12]2[C:29]3[N:28]=[CH:27][N:26]=[C:16]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]=3[N:14]=[CH:13]2)[C@@H:6]1[OH:30])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Agent: CN(C)c1ccncc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 12 h
Yield: 49 %

Procedure:
Compound 110 (11.17 g, 27.84 mmol) was dried over P2O5 under vacuum at 40° C., then dissolved in dry CH2Cl2 (56 mL, sure seal from Aldrich). 4-dimethylaminopyridine (0.34 g, 2.8 mmol, triethylamine (23.82 mL, 167 mmol) and t-butyldiphenylsilyl chloride were added. The reaction mixture was stirred vigorously for 12 hr. Reaction was monitored by TLC (ethyl acetate:hexane 1:1). It was then diluted with CH2Cl2 (50 mL) and washed with water (3×30 mL). Dichloromethane layer was dried over anhydrous Na2SO4 and evaporated to dryness. Residue purified by flash chromatography (ethyl acetate:hexane 1:1 as eluent) to get 111 as a white foam (8.85 g, 49%). Rf 0.35 (ethyl acetate:hexane, 1:1)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: CCOP(=S)(Cl)OCC
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=S)(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and diethyl chlorothiophosphate (410 mg, 2.2 mmol) were dissolved in acetonitrile (15 ml), and potassium carbonate (430 mg, 3.1 mmol) was added thereto. The mixture was stirred at room temperature for 2 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (362 mg, 82%) as white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:16]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[OH:30][CH:31]1[CH2:36][CH2:35]C(=O)[CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:16]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2].[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:16]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C)C3)cc1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2CCC(O)CC2)C3)cc1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
and 1-ethyl-3-(4-(7-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (yf): A mixture of compound 1 (200 mg, 0.52 mmol) and 4-hydroxycyclohexanone (97.9 mg, 0.85 mmol) in a mixed solvent of DCE/DMF (3:5, 10 mL) was stirred at 70-80° C. under N2 for 20 min. The solution was cooled down to 0° C. and NaBH(OAc)3 (366.5 mg, 1.75 mmol) was added and the mixture was stirred at 70-80° C. under N2 for 1 h. The solution was concentrated under high vacuum and the residue was dissolved in DCM (10 mL) and the insoluble solid was filtered off. The mother liquor was dried over anhydrous Na2SO4 and concentrated to give the crude product which was purified by reverse-phase HPLC to give 1-ethyl-3-(4-(7-(4-hydroxy-cyclohexyl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (ye) (55.6 mg, 22%) and 1-ethyl-3-(4-(7-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (yf) (67.5 mg). 1H NMR of 41 (D6-DMSO, 400 MHz): δ 9.41 (s, 1H), 8.12 (d, J=4, 2H), 7.46 (d, J=8.8, 2H), 6.74-6.70 (m, 1H), 4.55-4.39 (m, 1H), 3.80-3.61 (m, 6H), 3.44-3.36 (m, 4H), 3.10-3.06 (m, 2H), 2.68-2.65 (m, 4H), 2.40 (s, 1H), 1.90-1.65 (m, 4H), 1.60-1.47 (m, 1H), 1.45-1.28 (m, 2H), 1.25-1.09 (m, 1H), 1.02 (t, J=7.2, 3H). LC-MS: m/z=+481 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][CH:9]=[C:8](O)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)([Br:15])=O.CN(C=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:15][C:8]1[CH:7]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=[N:10][CH:9]=1
Reactant: Oc1cnnc(N2CCCC2)c1
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Brc1cnnc(N2CCCC2)c1
Temperature: 110 °C
Yield: 82.7 %

Procedure:
6-(1-pyrrolidinyl)-4-pyridazinol (D47) (35 mg, 0.212 mmol) was suspended in toluene (2 mL), followed by addition of phosphorus oxybromide (121 mg, 0.424 mmol). The reaction mixture was heated to 110° C. for 2 hours. The reaction was cooled to RT followed by addition of DMF (2.0 mL). The reaction was then heated at 110° C. again for 2 hours. Reaction mixture was allowed to cool to RT, and then poured onto crush ice portionwise with stirring. The mixture was neutralized with 5M NaOH and then extracted with ethyl acetate (3×20 mL). The combined organics were dried and concentrated down to give the title compound (40 mg) which was taken on to the next step without purification. LCMS (A): m/z (M+H)+ 228/230, C8H10BrN3 requires 227/229 (acidic).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Clc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(Cl)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), 4-chlorophenethyl bromide (0.24 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (15 ml) was heated under reflux for 7 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a solid which was recrystallised from aqueous methanol to give the title compound, yield 0.24 g, m.p. 188°-190° C.