Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38](Cl)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>O1CCCC1>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are reacted with 221 mg (0.96 mmol) of quinoline-8-sulfonyl chloride and 0.33 ml (4.08 mmol) of pyridine in 8 ml of tetrahydrofuran overnight.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(C2OCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a tetrahydrofuran (200 mL) solution of 4-[1,3] dioxolane-2-ylbenzaldehyde (6.32 g, 35.5 mmol) described in Manufacturing Example 73-1-1, aniline (2.08 mL, 35.5 mmol) and acetic acid (10.2 mL, 178 mmol) was added sodium triacetoxyborohydride (15 g, 71 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.16 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCC(=O)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 3′-chloropropiophenone (50.0 g, 297 mmol) in acetonitrile (595 mL) was added bromine (16.67 mL, 327 mmol) at room temperature. The reddish-yellow solution was allowed to stir for 18 h at room temperature. The solution was concentrated in vacuo to provide a reddish solid. The crude material was dissolved in 400 mL of ethyl acetate and washed with 400 mL of water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 72.6 g (98%) of crude product. 1H NMR (CDCl3) δ1.90 (d, J=6 Hz, 3H), 5.21 (q, J=6 Hz, 1H), 7.37-7.88 (m, 3H), 7.98 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11]([CH:13]=O)=O>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[C:4]([N:5]=1)=[N:9][CH:11]=[CH:13][N:10]=2
Reactant: Nc1nc(Cl)cc(Cl)c1N
Reactant: O=CC=O
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(Cl)c2nccnc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4.81 g (27 mmol) 4,6-dichloro-pyridine-2,3-diamine (synthesis described in J. E. Schelling, C. A. Salemink, Rec. Tray. Chim. Pays-Bas 91, 650 [1972]) in 50 ml THF was treated with 5.22 g (27 mmol) of a 30% solution of glyoxal in water and the mixture was stirred for 3 days at room temperature. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and diluted sodium carbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent yielding 6,8-dichloro-pyrido[2,3-b]pyrazine as off-white fine needles; HPLC/MS (B): 1.93 min, [M+H] 200.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].CO[C:23](=[O:40])[CH:24]([OH:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23](=[O:40])[CH:24]([OH:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(O)C(=O)N(CCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-dodecylamine (1.00 g, 0.0039 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyhexadecanoate (1.12 g, 0.0039 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.9 g). The waxy solid was recrystalized from hot hexane (yield=1.26 g).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:13]2[CH:8]([NH:9][CH2:10][CH2:11][N:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:6]1[C:7](=[O:14])[CH:8]2[C:13](=[N:12][CH2:11][CH2:10][NH:9]2)[N:4]([CH3:3])[C:5]1=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: CN1C(=O)NC(=O)C2NCCN=C21
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCN1C(=O)C2NCCN=C2N(C)C1=O
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1-methyl-2,4-dioxotetrahydropteridine (inventive compound no. 1426). 1-Methyl-4,5-diaminouracil (13.6 g; 59.4 mole) was suspended in water (150 mL) and converted to its hydrochloride by drop-wise addition of concentrated hydrochloric acid unitl the solution is strongly acidic. Glyoxan sodiumbisulphite (20.4 g; 71.8 mmol) was then added and the reaction mixture refluxed for 30 minutes. The reaction mixture was cooled to room temperature and the precipitated 1-methyl-2,4-dioxotetrahydropteridine isolated by filteration, yielding 6.5 g (62%). Sodium hydride (95%,) (0.575 g, 24 mmol) was added to a solution of 1-methyl-2,4-dioxotetrahydropteridine (3.56 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with ethyl acetate (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant to yield 5 g (94% yield) of 3-(10-undecenyl)-1-methyl-2,4-dioxotetrahydropteridine (inventive compound no. 1421). A solution of 3-(10-undecenyl)-1-methyl-2,4-dioxotetrahydropteridine (3.3 g, 10 mmol) and m-chloroperoxybenzoic acid (5.13 g; 15 mmol) (50% by wt) in dichloromethane (50 mL) was stirred for 5 hours. The reaction mixture was diluted with 40 mL of dichloromethane and washed successively with 20% aqueous sodium sulphite solution (20 mL), saturated sodium bicarbonate solution (20 mL), water (30 mL) and brine solutions (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 40% petroleum ether/ethyl acetate eluant to yield 2.61 g (75% yield) of 7-(11,10-Oxidondecyl)-1-methyl-2,4-dioxotetrahydropteridine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][C:5]=1[CH3:28].I[CH3:30]>CN(C)C=O>[CH3:3][C:4]1[C:12]2[C:11]([O:13][CH:14]3[CH2:15][CH2:16][CH:17]([N:20]([CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:18][CH2:19]3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][C:5]=1[CH3:28]
Reactant: CI
Reactant: Cc1sc2ncnc(OC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(OC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2c1C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Sodium hydride (220 mg, 9.17 mmol, 3.46 equiv) was added to a solution of tert-butyl N-[4-([5,6-dimethylthieno[2,3-d]pyrimidin-4-yl]oxy)cyclohexyl]carbamate (1.0 g, 2.65 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL) in several batches at 0° C. and the reaction mixture was stirred for 30 min. To this reaction mixture was added iodomethane (450 mg, 3.17 mmol, 1.20 equiv) dropwise at room temperature. The reaction mixture was stirred for 1 h at 30° C. and then quenched by the addition of 5 mL of water. The resulting solution was diluted with 50 mL of water, extracted with 2×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.6 g (58%) of tert-butyl N-[4-([5,6-dimethylthieno[2,3-d]pyrimidin-4-yl]oxy)cyclohexyl]-N-methylcarbamate as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=Cc1ccccc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCOCC3)Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
6-Amino-2-butoxy-9-[3-(3-morpholin-4-yl-propylamino)-propyl]-7,9-dihydro-purin-8-one (0.1 g), Benzaldehyde (0.03125 g, 0.03005 ml) were combined in NMP (1.5 mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.078 g) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with methanol and purified by RPHPLC to give the title compound (0.068 g)
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH2:13])[CH2:10][CH:9]=[CH:8]1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Cl:1][C:2]([Cl:15])([Cl:16])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH:13][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:10][CH:9]=[CH:8]1
Reactant: NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl

Procedure:
An 7.8 g. quantity of crude (IR,5S)-2,2,2-trichloroethyl-5-(aminooxy)-2cyclopentene-1-carbamate is dissolved in 25 ml. of tetrahydrofuran and 6.15 g (25 mm) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile and the mixture stirred for 22 hours at room temperature, 20 hours at 50° C., 72 hours at room temperature and then evaporated in vacuo. The residue is chromatographed over 900 g. of silica gel eluted with (15-85) ethylacetate-toluene. Three hundred ml. fractions are collected. The product is found in fractions 10-12. Evaporation and recrystallization of the residue from Skellysolve B yields (IR,5S)-2,2,2-trichloroethyl-5-[[[(t-butyloxy)carbonyl]amino]oxy]-2-cyclopentene-1-carbamate m.p. 83°-84° C. as a white solid.
Reaction SMILES: CN(C)C=O.CC(C)([O-])C.[Na+].[CH3:12][CH2:13][O:14][C:15]([CH:17](P(OCC)(OCC)=O)[CH3:18])=[O:16].[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>O>[CH3:18][C:17](=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=1)[C:15]([O:14][CH2:13][CH3:12])=[O:16]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To dimethylformamide (1802 ml) that had been cooled to −10° C. was added sodium tert-butoxide (528.6 g) and the solution was stirred at −5 to 0° C. for 30 min. Triethyl 2-phosphonopropionate (1310 g) was added dropwise thereto at 10° C. or below. The solution was stirred at 2 to 5° C. for 1 hr, and 4-methylbenzaldehyde (600.8 g) was added dropwise thereto at 10° C. or below and the solution was stirred at room temperature for 1 hr. Water was added thereto and the solution was extracted with toluene. The extract was washed with water and the solvent was distilled off to give the title compound as an oil (1009 g, yield 98.8%).
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH3+:14])[CH2:10][CH2:9]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.OS([O-])(=O)=O.[K+].CC(OC)(C)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: [NH3+][C@H]1CC[C@H](CCCCCBr)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (3.04 mmol) of trans-4-(5-Bromo-pentyl)-cyclohexylammonium bromide in 12 ml CH2Cl2 was first cooled at 0° C., treated with 0.8 g (3.27 mmol) 4-(trifluoromethyl)benzenesulfonylchloride and then with 1.2 ml (7.01 mmol; 2.3 equivalents) of Hünig's base (during 30 min). After total 1.5 h at 0° C., the mixture was dissolved in aqueous 10% KHSO4/TBME (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.38 g crude product which was crystallized (CH2Cl2/hexane) to give 1.26 g (91%) of pure trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 454 (M−H−, 1Br).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13](O)[N:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([Cl:21])[N:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc2c(nn1)CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc2c(nn1)CN(Cc1ccccc1)CC2
Temperature: 85 °C

Procedure:
To a slurry of 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-c]pyridazin-3-ol (7 g, 29.1 mmol) in toluene (50 ml) is added POCl3 (7 ml). The resulting mixture is heated at 85° C. for 3 hr. The mixture is cooled to 0° C. and is neutralized with saturated NaHCO3 solution. The mixture is extracted with EtOAc (100 ml×2). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by silica gel chromatography (EtOAc/4% TEA) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>CCOCC.O.[Cu]Cl.[Cu]>[CH3:19][C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:20])[C:17]#[CH:18]
Reactant: C#CC(C)(C)Cl
Reactant: Nc1ccccc1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC(C)(C)Nc1ccccc1
Temperature: 15 °C

Procedure:
A mixture of aniline (21.8 g, 234 mmol) and triethylamine (26.6 g, 263.3 mmol) in 100 mL ether, 25 mL water, 0.2 g copper(I) chloride and 0.2 g copper bronze was prepared under nitrogen in a three-neck flask equipped with mechanical stirrer. 3-Chloro-3-methyl-1-butyne (20 g, 195 mmol) in ether (25 mL) was slowly added with stirring while maintaining an inside temperature at 10-20° C. After stirring for an additional 2 hours at room temperature, the mixture was poured into a mixture of 200 mL ether and 100 mL water. The ethereal layer was washed with cold water, dried for 15 minutes over anhydrous potassium carbonate and filtered, redried with potassium hydroxide pellets overnight. The solution was filtered and concentrated under reduced pressure.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:27][C:26](C)(N3CCCC3)C2)[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[CH3:42]O>Cl.O1CCOCC1>[Cl:34][C:19]1[N:20]=[C:21]([NH:24][CH:27]([CH3:26])[CH3:42])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CC(C)(N3CCCC3)C2)c1F
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)nc(NN)c1F

Procedure:
A solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.225 g, 0.37 mmol) in MeOH (6 mL) and 4.0M HCl in dioxane (4 mL) was stirred at room temperature for 3 days. The solvent was then removed in vacuo, providing the crude 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine, presumably as the tri-HCl salt. LCMS: (M+H)+: 301.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[N:16][CH:17]=3)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(Cl)nc21
Reaction time: 0.33 h

Procedure:
To a mixture of NaH (1.3 mg, 37.6 mmol, 60%) in DMF (80 mL) was added slowly the solution of crude 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 30 supra) (5.83 g, 18.8 mmol) in DMF (40 mL) at 5° C. The ice-bath was removed and the mixture was stirred for 20 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (4.06 g, 24.4 mmol) was added. This solution was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NH4Cl and dichloromethane (3×20 mL). The combined organics was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 60 g, 200-300 mesh, eluting with ethyl acetate:petroleum ether, 1:10) to give 3-(6-bromo-pyridin-2-yl)-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 4.9 g, 84%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(Cl)Cl>[CH2:34]([NH:36][C:37]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
1-(2-Phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2. At four 15 min. increments, 10 μL (0.47 equiv), 5 μL (0.24 equiv), 2.1 μL (0.1 equiv) and 2.1 μL (0.1 equiv) of ethyisocyanate were added dropwise, respectfully. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2; dry loaded with silica gel, eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.64), 8.29 (1H, d, J=8.38), 8.20 (2H, dd, J=1.52, J=1.10), 7.97 (2H, m), 7.87 (1H, dd, J=1.71, J=1.71), 7.53 (4H, m), 7.24 (1H, d, J=5.26), 7.08 (1H, d, J=5.23), 4.38 (1H, t), 3.97 (2H, d, J=13.44), 3.28 (2H, m), 2.96 (2H, d, J=7.12), 2.79 (2H, t), 2.20 (1H, m), 1.80 (2H, d, J=10.60), 1.36 (2H, m); MS (ES+): m/z 506.07/507.08 (50/25) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](OCC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C:13](=[O:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: O=C1Cc2cc(OCc3ccccc3)ccc2N1
Product: CCOC(OCC)N1C(=O)Cc2cc(OCc3ccccc3)ccc21
Reaction time: 3 h
Yield: 73 %

Procedure:
A mixture of 5-benzyloxyoxindole (1.88 g, 7.9 mmol), (EP 0636608 A1), and triethyl orthoformate (180 ml) was heated at reflux with stirring for 3 hours. The volatiles were removed by evaporation and the residue was purified by column flash chromatography using petroleum ether/ether (7/3) as eluent. Evaporation of the solvents lead to a crystalline material which was collected by filtration and dried under vacuum to give 5-benzyloxy-1-diethoxymethyloxindole (1.96 g, 73%).