Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH3:28])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[OH:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH3:28])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1nc2c(c(=O)n(CCCC[C@@H](C)O)c(=O)n2C)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
A solution of (R)-1-(5-Acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (500 mg) in methanol (20 ml) was combined with hydrogen chloride in ether (1 M, 2.5 ml) and stirred at room temperature for 12 hours. After evaporation of the solvent under reduced pressure, the residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (30 ml), dried over magnesium sulfate and concentrated under reduced pressure to provide (R)-1-(5-hydroxyhexyl)-7-benzyl-3,8-dimethylxanthine (420 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(Br)C1C=CC=CC=1>CS(C)=O.CCOCC.O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Cc1ccccc1CBr
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
9-amino-3,4-dihydroacridin-1(2H)-one (7.63 g) was suspended in 75 ml of dimethylsulfoxide and 5 g of pulverized 85% potassium hydroxide was added. After 45 minutes a homogeneous solution was obtained to which was added 7.0 g of 2-methylbenzyl bromide. The reaction mixture was stirred for 30 minutes and then additional 2.0 g of the benzyl bromide was added. After 60 more minutes 300 ml of water and 30 ml of ether were added to the reaction. The precipitated product was filtered off and washed with additional ether, then flushed over a short magnesium silicate column with ethyl acetate. After evaporating the solvent, the product was again washed with cold ether to give 7.21 g of product.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[NH:4][C:5]([C:23](F)([F:25])[F:24])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:25][CH:23]([F:24])[C:5]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:28])([F:1])[F:27])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1CC(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC(C)C
Yield: 50.3 %

Procedure:
A mixture of 10.0 g (0.0240 mole) of diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-isobutyl-3,5-pyridinedicarboxylate, 3.65 g (0.0240 mole) of DBU and 150 ml of THF is held at reflux for 18 hours and concentrated. The residue is dissolved in ether and washed with diluted hydrochloric acid, dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 0.1 torr to give 4.80 g (50%) of the desired product as an oil, nD25 1.4436.
Reaction SMILES: Br[CH:2]([CH3:11])[CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[CH3:11][CH:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: [C-]#N
Reactant: Cc1ccc(CCC(C)Br)o1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CCC(C)C#N)o1
Reaction time: 16 h

Procedure:
A solution of 2-(3-bromobutyl)-5-methyl-furan (20.5 g) and 13 g KCN in 100 ml of dry dimethyl sulphoxide was heated during stirring for 16 hours at 50°-55° C. The mixture was cooled, diluted with water and extracted using ether. The extracts were washed with water, dried on anhydrous MgSO4 and boiled down under vacuum. The residue was subjected to chromatographic adsorption over silicagel with hexane/ethyl acetate (9:1) and gave 14.6 g dl-2-methyl-4-(5-methyl-2-furyl)-butane nitrile.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7](=[O:14])[CH2:8][N:9](C=O)[CH:10]=[O:11])=[CH:5][CH:6]=1.[OH-].[K+].C(O)C>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:14])[CH2:8][NH:9][CH:10]=[O:11])=[CH:5][CH:6]=1
Reactant: O=CN(C=O)CC(=O)c1ccc(Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=CNCC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the crude crystal of 2-chloro-5-(diformylaminoacetyl)-thiophene were added potassium hydroxide (0.60 g), ethanol (70 ml) and tetrahydrofuran (40 ml), and the mixture was stirred at room temperature for one hour. After removing the solvent under reduced pressure, tetrahydrofuran (150 ml) and anhydrous magnesium sulfate were added to the residue, and insoluble material was removed by filtration and washed with tetra-hydrofuran. The filtrate and the washed solution were combined and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether-ethyl acetate to obtain 2-chloro-5-(formylaminoacetyl)thiophene (14.81 g) as pale brownish crystal.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C(N1[CH:27]=[CH:26]N=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:32][C:33]([OH:35])=[O:34].C([K])C>C1COCC1>[C:12]([O:11][C:9]([NH:1][C@@H:2]([CH:3]([CH3:4])[CH3:5])[C:6](=[O:8])[CH2:32][C:33]([O:35][CH2:26][CH3:27])=[O:34])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(=O)O
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a stirred solution of compound Boc-Val-OH (3.11 g, 14.3 mmol) in THF (40 mL) at rt was added 1,1′-carbonyldiimidazole (3.48 g, 21.5 mmol). The mixture was stirred at rt for 1 h, then magnesium chloride (1.36 g, 14.3 mmol) and ethyl potassium malonate (2.44 g, 14.3 mmol) were added successively. The mixture was then heated to 50° C. and stirred for 15 h. The mixture was cooled to rt and quenched with 1 N HCl (100 mL). The aqueous phase was extracted with EtOAc (3×100 mL), then the combined organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to afford ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (3.53 g, 86% yield) as a yellow oil. LC-MS tR=0.91 min in 1 min chromatography, MS (ESI) m/z 288.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 5.08 (d, J=8.4 Hz, 1H), 4.33 (dd, J=4.4 Hz, 8.8 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 2.27-2.17 (m, 1H), 1.44 (s, 9H), 1.27 (t, J=7.2 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(=NN[C:16]1[CH:17]=[C:18]([CH2:37][N:38]([CH3:40])[CH3:39])[S:19][C:20]=1[CH:21]=[N:22][N:23]=C(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:40][N:38]([CH3:39])[CH2:37][C:18]1[S:19][C:20]2[CH:21]=[N:22][NH:23][C:16]=2[CH:17]=1
Reactant: CN(C)Cc1cc(NN=C(c2ccccc2)c2ccccc2)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cc2[nH]ncc2s1
Temperature: 85 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To [4-(N′-Benzhydrylidene-hydrazino)-5-(benzhydrylidene-hydrazonomethyl)-thiophen-2-ylmethyl]-dimethyl-amine [Intermediate (4)] in ethanol (100 mL) was added 50 mL of concentrated hydrochloric acid. The dark red mixture is stirred at 85° C. for 2 hours. Water is added followed by solid sodium carbonate until pH is slightly basic. The reaction mixture is then extracted twice with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is chromatographed (ethyl acetate—1.0M ammonia in methanol, 90:10 as eluant) to produce dimethyl-(1H-thieno[3,2-c]pyrazol-5-ylmethyl)-amine [1.06 g, 45% Intermediate (5)] as a brown solid. LC/MS: RT=0.4 minutes, 182.09 m/e (M+H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: O=C1N(CCl)CCC(O)N1c1nnc(C(F)(F)F)s1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCC(=O)OC1CCN(CCl)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hexanoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH3:40])[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:25]=[CH:26][C:13]([C:10]4[CH:11]=[CH:12][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:9]=4)=[CH:14][CH:15]=3)=[CH:19][CH:20]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4ccc(F)cc4)n3)cc2)cc1
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-phenoxy}-phenol and 5-bromo-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+531.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[S:3].Cl.[O-:11][Mn](=O)(=O)=O.[K+].[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>>[CH2:8]([O:7][C:5]([CH2:4][N:1]1[C:2](=[O:11])[S:3][N:20]([CH:17]([CH3:19])[CH3:18])[C:21]1=[O:22])=[O:6])[CH3:9]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)CN=C=S
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1c(=O)sn(C(C)C)c1=O

Procedure:
Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), isopropyl isocyanate (0.64 ml, 6.5 mmol).
Reaction SMILES: [H-].[Na+].[OH-:3].[Na+].[CH2:5]([NH2:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC[CH2:21][CH3:22]>>[CH2:5]([NH2:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:21]1[O:3][CH2:22]1
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: [H-]
Agent: [Na+]
Product: C1CO1
Product: CCCCCCCCCCCCN
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Into a 1-liter autoclave were introduced 300 g of the stearylamine obtained (total amine value: 210.2), an aqueous sodium hydride solution, and a 12% solution of a 50% aqueous sodium hydroxide solution. The amount of the aqueous sodium hydride solution introduced was 0.1 mol% based on the amine. After bubbling with nitrogen gas, the contents were heated to 160° C., and 205 g of ethylene oxide was forced into the autoclave at a rate of 10 g/min at the constant temperature. The amine/ethylene oxide molar ratio was 1/4.15. After completion of the feeding, the mixture was aged for 30 minutes. The obtained substance was discharged from the reactor and then purified by distillation to obtain the target ethylene oxide adduct of laurylamine (the number of moles of added ethylene oxide: 4.15).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[CH:18][N:17]=[C:16]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=4)=[N:23][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[NH:21][C:16]2=[N:17][CH:18]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To 4-[6-Bromo-2-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.380 g, 0.75 mmol) in dichloromethane (20 mL) at 0° C. was added slowly TFA (2 mL) and the reaction mixture was stirred at rt for 30 mins. TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and TFA was co-evaporated with CH3CN. The crude product was run trough a 5 g SCX cartridge and eluted with 0.1M NH3 in methanol. The compound was further triturated in ether/methanol 9/1 to give the title compound as a solid (0.228 g, 75%);
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added pentanoyl chloride (0.060 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 687 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[C:10]([CH3:11])=[N:9][O:8][C:7]=3[C:12]3([NH:15][C:16](=O)[C:4]=2[CH:3]=1)[CH2:14][CH2:13]3.C(Cl)[Cl:21].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:21][C:16]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=2[C:6]2[C:10]([CH3:11])=[N:9][O:8][C:7]=2[C:12]2([N:15]=1)[CH2:14][CH2:13]2
Reactant: ClCCl
Reactant: Cc1noc2c1-c1ccc(Cl)cc1C(=O)NC21CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1noc2c1-c1ccc(Cl)cc1C(Cl)=NC21CC1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a vial containing 8-chloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropan]-6(5H)-one (0.0631 g, 0.230 mmol) was added CH2Cl2 (1 mL). The reaction mixture was heterogeneous and to aid in solubility CHCl3 (0.5 mL) was added. To the homogeneous mixture was added phosphorous pentachloride (0.092 g, 0.442 mmol) in one portion at room temperature. The reaction mixture eventually turned heterogeneous again (˜<10 min) and LC-MS analysis after ˜30 min indicated complete consumption of starting material and formation of desired product. The mixture was diluted with EtOAc and aqueous 10% Na2CO3 (2.8 mL). After initial effervescence, the mixture was stirred for an additional 5-10 min, and the aqueous layer was extracted with EtOAc (3×). The combine organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to give yellow solids. The solids were filtered over a plug of silica and eluted with 30% EtOAc:70% Hexanes. The product 6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (61.8 mg, 0.211 mmol, 92% yield) was obtained as off-white solids. LC/MS m/z 293 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>COCCOC>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: COCCOC
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Stage 278.1), 240 mg, 0.728 mmol) was introduced in a microwave reactor together with 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (227 mg, 1.092 mmol) and DME (5 mL). The mixture was purged with argon for 5 min. Tetrakis-(triphenylphosphine)-palladium (42.1 mg) and 2 M Na2CO3 (1.31 mL) were added and the mixture was flushed with argon before being sealed. The RM was submitted to microwave irradiation at 150° C. 30 min. Then it was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound as a white solid (tR 1.03 min (conditions 2), MH+=376) 1H-NMR in DMSO-d6: 8.29 (s, 1H); 8.05 (d, 1H); 7.93 (s, 1H); 7.67 (s, 1H); 7.58 (d, 1H); 7.53 (d, 1H); 7.46 (d, 1H); 7.23 (d, 1H); 4.92 (q, 1H); 3.94 (s, 3H); 3.88 (s, 3H); 1.76 (d, 3H)).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])[O:17]CC)[OH:15])=O)C1C=CC=CC=1.O.C(O)C.[ClH:29]>>[ClH:29].[NH2:11][CH2:12][CH2:13][CH:14]([P:16]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:17])[OH:20])[OH:15]
Reactant: CCCCP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCP(=O)(O)C(O)CCN
Temperature: 25 °C

Procedure:
A suspension of 1.3 g of ethyl 3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate in 10 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. The clear solution is cooled to room temperature and washed with 1×50 ml of dichloromethane and 1×50 ml of ether. Evaporation of the aqueous layer affords a solid which is co-evaporated with 5×50 ml of water and 5×50 ml of absolute ethanol. Drying of the solid and crystallisation from ethanol affords 3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p. 147°-150°. Dissolution of the hydrochloride salt in ethanol and treatment with propylene oxide affords, after filtration and drying, 3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid, m.p. 123°-125°.
Reaction SMILES: [OH:1]O.[CH:3]1([C:6]2[N:10](C(=O)C)[N:9]=[C:8]([NH:14][C:15]3[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1.O>C1COCC1>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:14][C:15]3[C:20]([OH:1])=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2B2OC(C)(C)C(C)(C)O2)cc1C1CC1
Reactant: OO
Solvent: C1CCOC1
Solvent: O
Product: Oc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 8 %

Procedure:
30% H2O2 (10 mL) was added to the solution of 1-(5-cyclopropyl-3-(2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (200 mg, 0.45 mmol, 1.0 eq) in THF (5 mL) at 0° C. The mixture was stirred for 1 h and water was added. The solid was collected and dissolved in methanol (8 mL). To the solution was added 5 N NaOH (4 mL). The mixture was stirred for 2 h at room temperature and concentrated. To the residue was added ethanol and EtOAc. The emerged solid was filtered off. The filtrate was concentrated and the residue was recrystallized with CH2Cl2 and ethyl ether to give 4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-ol (Compound 55) (10 mg, 8% over 2 steps). LC-MS (m/z)=294.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.69-0.74 (m, 2H), 0.93-0.98 (m, 2H), 1.85-1.89 (m, 1H), 6.52 (bs, 1H), 7.40-7.47 (m, 3H), 7.93 (s, 1H), 8.22 (d, J=7.6 Hz, 2H), 8.41 (bs, 1H), 10.43 (bs, 1H), 12.09 (bs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([CH3:25])[CH2:10][CH2:11][O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][CH:9]([CH3:25])[CH2:10][CH2:11][O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC(C)C)nc2n1CC1CCOCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (143 mg) in dry DMF (2.42 mL) was added potassium carbonate (217 mg) and the mixture was stirred at 60° C. for 90 mins. The reaction was cooled and 4-(bromomethyl)tetrahydro-2H-pyran (77 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (30 mL) and extracted with water (2×15 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a clear viscous oil (52 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-methanesulfonylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 370 (M+H+, 100).