Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([CH2:15][CH:14]=[CH2:13])[C:6]#[N:7])[CH:8]=[CH:9][CH:10]=1
Reactant: C=CCBr
Reactant: N#CCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C#N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A solution of 3-chlorobenzyl cyanide (2.00 g, 13.2 mmol) in 15 mL of THF was added over 30 min to a suspension of sodium hydride (60% dispersion in mineral oil, 636 mg, 15.9 mmol) in 5.0 mL of dry THF. After stirring 2 h at room temperature, the mixture was cooled to -20 ° C., a solution of allyl bromide (1.14 mL, 1.59 g, 13.2 mmol) in 3.0 mL of THF was added, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was quenched with a solution of 1.6 g of ammonium chloride in 100 mL of water. The aqueous layer was extracted with 3×50 mL of ethyl ether and the combined organic layers were washed with 50 mL of brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 20-40% dichloromethane in hexane. Additional purification by flash column chromatography on silica gel, eluting with 5% ethyl ether in hexane gave 897 mg of the title compound as an amber oil. 1NMR (400 MHz, CDCl3): δ 7.36-7.30 (m, 3H), 7.25-7.21 (m, 2H), 5.78 (ddt, 1H, J=17, 10, 7 Hz), 5.21 (bd, 1H, J=10 Hz), 5.20 (dq, 1H, J=17, 1 Hz), 3.84 (t, 1H, J=7 Hz), 2.70-2.57 (m, 2K). Mass spectrum (EI): m/z=191 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1cccc(N)c1OC
Product: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1OC

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,3-dimethoxyaniline by a procedure similar to Example 28 (84% yield). 1H NMR (CDCl3): 8.57 (s, broad, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.77-7.86 (m, 3H), 7.55-7.61 (m, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.73-6.75 (m, 1H), 4.00 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:17][C:18](=[O:21])[CH2:19]Cl)[C:9]2=[O:22])[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].[Na+].[I-]>CC(C)=O.ClCCl.O>[N:24]([CH2:19][C:18]([NH:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:22])=[O:21])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCC(N2Cc3c(NC(=O)CCl)cccc3C2=O)C(=O)N1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a stirred suspension of N-[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]-2-chloroacetamide (4.64 g, 13.8 mmol) in acetone (60 ml) was added sodium azide (1.35 g, 20.7 mmol). The mixture was heated to reflux for 18 hours. After 18 hours, to the reaction mixture was added NaI (2.05 g, 13.8 mmol) and additional sodium azide (0.90 g, 13.8 mmol). The mixture was heated at reflux for an additional 18 hours. The solvent was evaporated in vacuo to give an off-white solid which was slurried in a mixture of dichloromethane (50 ml) and H2O (50 ml). This slurry was filtered to give 4.39 g (93%) of product: 1H NMR (DMSO-d6) δ 11.50–9.52 (bs, 2H), 7.87–7.84 (m, 1H), 7.59–7.50 (m, 2H), 5.17 (dd, J=5.0 and 13.1 Hz, 1H), 4.44 (d, J=17.6 Hz, 1H), 4.34 (d, J=17.6 Hz, 1H), 4.13 (s, 2H), 3.00–2.86 (m, 1H), 2.65–2.59 (m, 1H), 2.44–2.29 (m, 1H), 2.07–2.02 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.Cl.[O:42]([NH2:44])[CH3:43].CCN(C(C)C)C(C)C>C(O)C.CCOC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:43][O:42]/[N:44]=[C:27]1\[CH2:26][CH:25]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:24]2[N:23]([N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:12]4[CH:13]=[C:9]([Cl:8])[N:10]=[CH:11]4)=[C:15]([O:39][CH3:40])[CH:16]=3)[N:38]=2)[CH2:29][CH2:28]\1
Reactant: CON
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CO/N=C1/CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in ethanol (1.1 mL) was added methoxylamine hydrochloride (35.8 mg, 0.428 mmol) and DIPEA (112 μL, 0.643 mmol). The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Mg SO4, filtered and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the TFA salt of the titled compound as a mixture of E/Z isomers (76.7 mg, 56% yield). LC-MS (M+H)+ 496.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.52-9.79 (1 H, m), 8.02 (1 H, s), 7.25-7.36 (1 H, m), 7.05-7.25 (7 H, m), 4.46-4.73 (3 H, m), 3.81-3.97 (6 H, m), 2.95-3.24 (3 H, m), 2.84 (1 H, t, J=5.8 Hz).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5](=[O:25])[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C>[OH-].[K+].CO>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[S:7][C:6]([C:5](=[O:25])[C:4]([OH:26])=[O:3])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Yield: 90 %

Procedure:
In potassium hydroxide solution (3.1 mL) was added dropwise with stirring to a chilled solution of 5-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetic acid ethyl ester (1.13 g) in methanol (7 mL). Almost immediately the potassium salt precipitated from the solution as a colorless solid which was filtered off and washed with methanol. The solid was partitioned between dichloromethane (100 mL) and 0.1N hydrochloric acid (35 mL) and after all solids had dissolved, the organic layer was washed with water, dried over anhydrous sodium sulfate (Na2SO4) and evaporated to yield 0.94 g of 5-[[2-(2naphthalenyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetic acid as a yellow-orange solid. Crystallization of the acid from benzene-hexane furnished the title compound as a yellow solid, mp 152°-154 ° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:20][CH3:21])=[CH:7][C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:19]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:21][O:20][C:6]1[C:5]([CH2:3][OH:2])=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:12][C:8]=2[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)sc2cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc2sc(-c3ccccc3)nc2cc1CO
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 1 liter round bottom flask was charged with 12.88 grams (45.2 mmol) of methyl-6-methoxy-2-phenyl-5-benzothiazolecarboxylate (as part of a mixture of regioisomeric carboxylates) in 600 mL of dry tetrahydrofuran (THF). This solution was cooled to 0° C. and treated with 67.8 mL (67.8 mmol) of a 1.0M solution of lithium aluminum hydride in THF. The dark reaction mixture was stirred for 5 hours under nitrogen. The reaction was worked up by the careful dropwise addition of a saturated aqueous solution of sodium sulfate until a granular precipitate formed. The suspension was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and saturated brine solution. The organic phase was dried over sodium sulfate and evaporated. This product was used directly in the next step. (10.94 grams crude yield)
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17](=[O:25])[C:16]2=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.C(N(CC)C(C)C)(C)C>>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:34]=[CH:33][N:32]=1
Reactant: Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3ccccc3)c(=O)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3C#N)n(-c3ccccc3)c(=O)c12
Yield: 69.1 %

Procedure:
(S)-2-(1-Amino-3-(benzyloxy)propyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (24 mg, 0.06 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (10 mg, 0.06 mmol), N,N-diisopropylethylamine (59 μl, 0.34 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to obtain 21 mg (73% yield) of the title compound as a yellow solid. Purity 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:15])[CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([O:9][CH3:20])=[O:8])=[C:5]([CH3:15])[CH:4]=1
Reactant: COc1cc(C)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1C
Yield: 89 %

Procedure:
To 4-methoxy-2-methyl-5-nitrobenzoic acid (1.06 g, 5 mmol) in methanol (10 mL) was added thionyl chloride (0.36 mL, 5 mmol) dropwise. The mixture was heated to reflux for 5 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give methyl 4-methoxy-2-methyl-5-nitrobenzoate (998 mg, 89%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=226 at 3.25 min. 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 6.91 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH:7]([CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:8](OCC)=[O:9])(=[O:5])[CH3:4]>C(O)C.O>[OH:9][CH2:8][CH:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)C(Cc1cnccn1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(CO)Cc1cnccn1
Temperature: 20 °C
Reaction time: 18 h
Yield: 157.3 %

Procedure:
2.8 g of sodium borohydride are added to a solution of 8.5 g of ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate in 100 cm3 of ethanol and the mixture is then stirred at a temperature in the region of 20° C. After 18 hours, the reaction medium is taken up in 50 cm3 of water and 100 cm3 of dichloromethane and the aqueous phase is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 11 g of N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]acetamide are obtained in the form of a brown paste [1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4 δ in ppm): 1.71 (s: 3H); 2.81 (dd, J=14.5 and 9 Hz: 1H); 3.03 (dd, J=14.5 and 5 Hz: 1H); 3.35 (dd, J=11 and 6 Hz); 3.42 (dd, J=11 and 5 Hz: 1H); 4.11 (mt: 1H); 7.75 (residual d, J=8.5 Hz: 0.5H); 8.45 (d, J=2.5 Hz: 1H); 8.50 (broad s: 1H); 8.53 (mt: 1H)]).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]#[C:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1>[Pd].CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#CCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN3C(=O)c4ccccc4C3=O)ccc21
Yield: 86.9 %

Procedure:
10% Palladium on carbon(0.52 g) was added to a methanol solution (50 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.2 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound(1.93 g) as a brown solid.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([O:7][CH:8]([CH2:28][O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:9][O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:6])[CH3:3].[I-].[Na+].[C:49]([NH:52][C:53]1[C:54]([I:68])=[C:55]([C:59]([I:67])=[C:60]([NH:63][C:64](=[O:66])[CH3:65])[C:61]=1[I:62])[C:56]([O-:58])=[O:57])(=[O:51])[CH3:50].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.ClCCl>[C:64]([NH:63][C:60]1[C:59]([I:67])=[C:55]([C:54]([I:68])=[C:53]([NH:52][C:49](=[O:51])[CH3:50])[C:61]=1[I:62])[C:56]([O:58][CH:2]([O:4][C:5]([O:7][CH:8]([CH2:28][O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:9][O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:6])[CH3:3])=[O:57])(=[O:66])[CH3:65]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 50 °C
Reaction time: 120 h

Procedure:
2-(1-Chloroethoxycarbonyl)-1,3-dipalmitoylglycerol (1.00 g, 1.43 mmol) and sodium iodide were dissolved in a solution of potassium 3,5-diacetylamino-2,4,6-triiodobenzoate (0.88 g, 1.35 mmol) in DMF (10 ml). After 5 days stirring at 50° C. 18-Crown-6 (40 mg, 0.15 mmol) was added to the mixture which was then stirred at 50° C. for a further 3 days. The reaction mixture was diluted with dichloromethane, washed 4 times with a saturated sodium bicarbonate solution, twice with water, dried over sodium sulphate and evaporated. The residue was purified by column chromatography on silica gel using heptane-ethyl acetate (1:2) as eluent.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].Br.[OH-:23].[NH4+].Cl>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:5]([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:23]
Reactant: [OH-]
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Yield: 56.3 %

Procedure:
To a 250 mL flask was charged 38.16 g (0.119 mole) of alpha-n-butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-propane-nitrile followed by 100 mL (0.63 mole) of 48% hydrobromic acid. The mixture was stirred at reflux for 48 hours after which GLC indicated disappearance of the starting material. The reaction was cooled to room temperature and neutralized with concentrated ammonium hydroxide (100 mL) to pH 8 and then to neutral pH with concentrated hydrochloric acid. A gummy oil formed which was taken up with 200 mL of ethyl acetate. The aqueous was extracted twice more with 200 ml portions of ethyl acetate and the combined ethyl acetate portions were then washed three times with 100 mL portions of water. The organic phase was dried and concentrated to give a tan solid which was recrystallized from ethyl ether. The product was filtered and gave 22.78 g (56.3% yield) of a solid, Example 162 of Table 1.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: OC1CCNCC1
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccn1
Yield: 46 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and 4-hydroxypiperidine to give the title compound in 46% yield; NMR Spectrum: 1.20 (t, 3H), 1.32-1.39 (m, 2H), 1.66-1.69 (m, 2H), 2.16 (t, 2H), 2.67 (q, 2H), 2.75-2.81 (m, 4H), 4.39 (t, 2H), 4.52 (d, 1H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.40 (m, 1H), 7.44 (d, 1H), 7.50-7.55 (m, 2H), 7.85 (td, 1H), 8.24 (s, 1H), 8.25 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 490 (MH+).
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCC1.N1CCCC1>>[N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:12][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: N#CC1(N2CCCC2)COC1
Solvent: C1CCNC1
Product: N#CC1(N2CCCC2)CCC1

Procedure:
The title compound, colorless liquid, MS: m/e=151.1 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and pyrrolidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[N:36]1([C:7](=[O:9])[CH2:6][O:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:12]=[CH:11][CH:10]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: O=C(O)COc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1cccc(O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-hydroxyphenoxy)acetic acid (246 mg) in DMF (10 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (336 mg), 1H-benzotriazol-1-ol hydrate (268 mg) and morpholine (153 μL) at room temperature, followed by overnight stirring at room temperature. The solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(2-(morpholin-4-yl)-2-oxoethoxy)phenol (305 mg).
Reaction SMILES: C(=N[C@H](C(OCC1C=CC=CC=1)=O)CC(C)C)C1C=CC=CC=1.[CH2:24]([O:31][C:32]([C@@H:34]([N:39]1[C@H:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:41]([N:49]=[N+:50]=[N-:51])[C:40]1=[O:52])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]([C@@H:34]([N:39]1[C@@H:42]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:41]([N:49]=[N+:50]=[N-:51])[C:40]1=[O:52])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)N1C(=O)[C@@H](N=[N+]=[N-])[C@H]1c1ccccc1
Agent: CC(C)C[C@H](N=Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccccc1
Yield: 77.3 %

Procedure:
Using N-benzylidene-1(S)-benzyloxycarbonyl-3-methylbutylamine (3.62 g., 11.7 mmol) as a starting material, the reaction, separation and purification were carried out under the same conditions as in Referential example 7 to give a mixture of 1-(1(S)-benzyloxycarbonyl-3-methylbutyl)-3(S)-azido-4(R)-phenylazetidin-2-one and 1-(1(S)-benzyloxycarbonyl-3-methylbutyl)-3(R)-azido-4(S)-phenylazetidin-2-one (3.55 g., yield: 77.3%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=2)=[CH:11][C:10]=1[CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([NH:33]C(=O)OC(C)(C)C)[CH:30]=[N:31][CH:32]=1)=O)(C)(C)C.CO.[ClH:43]>O1CCOCC1>[ClH:23].[ClH:43].[ClH:23].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=2)=[CH:11][C:10]=1[CH2:25][CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29]([NH2:33])[CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Into a reaction flask were added tert-butyl {5-[2-(2-[(tert-butoxycarbonyl)amino]-5-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)ethyl]pyridin-3-yl}carbamate (0.44 g, 0.75 mmol), methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4.0 M). The reaction mixture was stirred at rt overnight and concentrated under vacuum to give the desired product as a white powder (0.40 g, 98%). LCMS for C18H19Cl2N6 (M+H)+: m/z=389.0, 391.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1COCCN1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Solvent: CCC(C)O
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 105 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 500 mL volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 95.0 g (0.354 mol) of 6-methoxy-7-(3-chloropropoxy)-quinazolin-4-one, 154.2 g (1.77 mol) of morpholine, and 380 mL of sec-butyl alcohol. The resulting mixture was heated to 105° C. under stirring for 18 hours. After the reaction was complete, 380 mL of methanol was added to the reaction mixture. The resulting mixture was stirred at 70° C. for 30 minutes, and cooled to room temperature. The mixture was then stirred for 30 minutes at room temperature. The precipitated crystalline product was filtered, placed in 190 mL of methanol and stirred for washing, again filtered, and dried at 60° C. under reduced pressure to give 104 g (isolated yield: 92%, purity: 98.81% in terms of area percentage determined by high performance liquid chromatography) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one as a white crystalline product.