Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.C([Li])CCC.[I:27]I>O1CCCC1.CCCCCC>[I:27][C:10]1[N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:5]2[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH:11]=1
Reactant: COc1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncnc2c1cc(I)n2S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [2.23 g, Reference Example 7] in tetrahydrofuran (35 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (5 mL, 1.6M) under inert atmosphere. The solution was stirred at −70° C. for 1 hour and iodine (2.05 g) was added. The reaction mixture was stirred at −70° C. for another 1 hour, allowed to reach room temperature and partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure to give the title compound (2.64 g) as an amorphous solid. MS: 430 [MH]+. LCMS (Method B) RT=4.15 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:26]=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nc(N3CCN(c4ccnc(Cl)n4)CC3)nc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (30.0 g, 0.104 mole), 2,4-dichloropyrimidine (17.3 g, 0.117 mole) and triethylamine (20.5 g, 0.203 mole) in ethanol (1200 ml) were heated at reflux for three hours. The solid which separated on cooling was filtered, slurried in hot isopropanol (500 ml), filtered and washed with hot methanol. The product was partitioned between 5% by volume methanol in methylene chloride and 10% (w/w) aqueous sodium carbonate solution, the organic layer separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The resulting solid was slurried in hot isopropanol, filtered and washed with hot isopropanol to afford 20 g. of the title compound, m.p. 266° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([S:45]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[NH:4][C:5]3=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[O:16])[CH2:9][CH2:10]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 40B (50 mg, 0.099 mmol) and benzenesulfonyl chloride (0.025 ml, 0.198 mmol) were reacted to generate the title compound as a white solid (25 mg, 0.037 mmol, 37% yield).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH2:12][CH3:13])[S:11][C:5]=2[N:4]=[CH:3]1.[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([CH2:12][CH3:13])[S:11][C:5]=4[N:4]=[CH:3]3)=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CCc1cc2c(=O)n(N)cnc2s1
Product: CCc1cc2c(=O)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)cnc2s1

Procedure:
3-Amino-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantane acetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm. 35 (t, J=7.5 Hz, 1H), 1.64-1.73 (m, 12H), 2.00-2.04 (m, 3H), 2.21 (s, 2H), 2.88 (qd, J=7.5, 1.2 Hz, 1H), 7.17 (t, J=1.2 Hz, 1H), 7.93 (s, 1H), 8.08 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2S.0.2H2O: C, 64.04; H, 6.83; N, 11.20. Found: C, 63.91; H, 6.68; N, 11.27.
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@@:4]2([O:6][CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=[O:23].C(Cl)Cl.[OH-].[Na+]>O>[OH:6][C@@:4]1([CH2:5][OH:23])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)([CH3:1])[CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@]2(CO2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@](O)(CO)C1
Temperature: 18 °C
Reaction time: 2.5 h

Procedure:
To a 3 L flask was added 1-{[(3R,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (94.7 g, 337 mmol). The material was azeotroped two times with EtOAc to remove any trace amounts of MeOH from the SFC. Next, to the residue was added DMF (731 mL) and water (731 mL). The solution was cooled to ˜18° C. (with an ice water bath). Next, a solution of TFA (51.9 mL, 673 mmol) in water (731 mL) added (pre-cooled to ˜10° C.). The entire solution was then cooled with an ice water bath to ˜10° C. The temperature was held around 10° C. for about 2.5 h then allowed to warm to RT and stir overnight. The next day, DCM (500 mL) was added, and the solution was made basic by slowly adding 6N NaOH. The mixture was added to a separatory funnel, the DCM separated and the aqueous layer diluted with 6N NaOH (300 mL), and then extracted with DCM (8×250 mL). The combined organic extracts were concentrated under reduced pressure to remove as much DMF as possible. The residue was dissolved in DCM (250 mL) and stirred at RT to crystallize the trans diol. After stirring overnight, the solution was cooled to ˜10° C., and the solids were filtered off, washed with DCM and dried under reduced pressure. This yielded 49.15 g of 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (trans diol) as a white solid. The filtrate (˜60 g material, a mixture of cis-diol, trans-diol, and elimination side products) was concentrated, loaded onto silica gel and split into 3 equal portions and purified on the ISCO RF (3×330 g column): 0-5% MeOH/DCM over 15 min, hold at 5% for 10 min, then 5-25% over 10 min, then hold at 25%. The trans diol product was combined with the solids from the crystallization and used without further purification. MS (m/z) 300.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][C:27]=1[Cl:28])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[N:24]([CH2:16][C:13]2[S:12][C:11]([C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH:8]=[CH:9][CH2:10]3)=[CH:15][CH:14]=2)[C:25]([CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][C:27]=1[Cl:28])=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CC=CC1
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1

Procedure:
Alkylation was carried out on 1-(5-chloromethylthiophen-2-yl)cyclopent-3-ene carboxylic acid ethyl ester (5) as described in Example 1, Step 5, using 2-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester (69) to yield the title compound (71).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH2:14][C:15]([CH2:20][OH:21])([CH3:19])[C:16]([OH:18])=[O:17].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([O:13][CH2:14][C:15]([CH2:20][O:21][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:19])[C:16]([OH:18])=[O:17])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(CO)(CO)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)OCC(C)(COC(=O)CCCCCCCCC)C(=O)O
Temperature: 25 °C

Procedure:
n-Decanoyl chloride (23.6 mL) was combined with 5.0 grams of 2,2-bis(hydroxymethyl)propionic acid and 100 mL of chloroform (filtered through activity I basic alumina). Triethylamine (17.1 mL) and 4-dimethylaminopyridine (2.28 grams) were then added and the resulting mixture was heated at reflux under nitrogen for 16 hours. The reaction was then cooled to room temperature and quenched with 200 mL of water. The solution was cooled to 0° C. and acidified to pH 3 with concentrated aqueous hydrochloric acid. The solution was extracted three times with methylene chloride and the combined methylene chloride layers were washed once with 1% aqueous hydrochloric acid and once with saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, filtered and the solvents removed in vacuo to yield 26.01 grams of a mixture of a yellow oil and solid. The mixture was chromatographed on silica gel eluting with hexane/ethyl acetate/acetic acid (95:4:1) to yield 20.6 grams of the desired product as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([C:24]2[CH:28]=[C:27]([CH:29]=O)[O:26][N:25]=2)([OH:23])[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>CO>[C:29]([C:27]1[O:26][N:25]=[C:24]([C:21]([OH:23])([CH3:22])[C:20]#[C:19][C:18]2[C:2]([F:1])=[CH:3][C:4]3[O:10][CH2:9][CH2:8][N:7]4[CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=[C:6]4[C:5]=3[CH:17]=2)[CH:28]=1)#[CH:31]
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
Dimethyl [1-(methylidyneimino)-2-oxopropyl]phosphonate (27.9 mg, 0.15 mmol, 1.00 equiv) in methanol (0.2 mL) was added dropwise to a stirred mixture of 9-fluoro-10-(3-(5-formylisoxazol-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (60 mg, 0.15 mmol, 1.00 equiv) and potassium carbonate (39 mg, 0.28 mmol, 2.00 equiv) in methanol (1.5 mL) at room temperature. The resulting mixture was stirred for 12 h at room temperature and the solids were filtered out. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, Water with 10 mmolNH4HCO3 and CH3CN (22% CH3CN up to 43% in 15 min, up to 95% in 2 min, down to 22% in 2 min); Detector, UV 254/220 nm to give 12.7 mg of the titled compound (21%) as a colorless solid.
Reaction SMILES: I[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1)[CH:17]=[CH2:16]
Reactant: [O-][n+]1nc(I)nc2cc3c(cc21)CCC3
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: C=CCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 85.1 %

Procedure:
Pd(PPh3)4 (0.89 g, 0.77 mmol) was added to a stirred, degassed solution of iodide 66 (4.80 g, 15.3 mmol) and allyltributyltin (5.2 mL, 16.9 mmol) in DME (100 mL), and the mixture stirred at reflux temperature for 8 h. The solvent was evaporated and the residue purified by chromatography, eluting with 10% EtOAc/pet. ether, to give 1-oxide 69 (2.96 g, 85%) as white solid: mp (EtOAc/pet. ether) 60-61° C.; 1H NMR δ 8.26 (s, 1H, H-9), 7.77 (s, 1H, H-5), 6.12-6.23 (m, 1H, H-2′), 5.29 (dd, J=17.1, 1.5 Hz, 1H, H-3′), 5.22 (dd, J=10.1, 1.3 Hz, 1H, H-3′), 3.77 (br d, J=6.9 Hz, 2H, H-1′), 3.08-3.14 (m, 4H, H-6, H-8), 2.21 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 164.1, 154.8, 149.0, 147.5, 133.0, 132.3, 122.7, 118.2, 114.3, 41.6, 33.2, 32.8, 25.7. Anal. calcd for C13H13N3O: C, 68.7; H, 5.8; N, 18.5. Found: C, 68.7; H, 5.9; N, 18.7%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10]=1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:19][N:18]=1
Reactant: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2n[nH]c3ncccc23)[nH]1
Yield: 46 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone (240 mg, 1 mmol) and hydrazine hydrate (0.7 mL) in ethanol (2 mL) was heated at 100–110° C. for overnight. The reaction was concentrated and purified on a silica gel column to give 97 mg (46%) of the titled compound as a light yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:1]([C:3](=[CH:15][N:16]([CH3:18])[CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1ccccc1
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1

Procedure:
A 10.0 g. amount of 2-cyanoacetanilide in 25 ml. of N,N-dimethylformamide dimethylacetal is heated on a steam bath for 2-6 hours. The reaction mixture volatiles are removed in vacuo and the resultant solid is dissolved in dichloromethane. The solution is passed through a short column of hydrous magnesium silicate, then n-hexane is added to the effluent until crystallization is noted. After cooling, the product is collected by filtration to give 2-cyano-3-dimethylamino-acrylanilide as colorless plates, m.p. 162.5°-164° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)Cl>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Br:26])[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(=O)OCC(COC(C)=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of acetic acid 3-acetoxy-2-(4-amino-phenyl)-propyl ester (Tetrahedron, 46(20), 7081, (1990), 1.2 g, 5.0 mmol) in DCM (50 mL), NBS (903 mg, 5.07 mol) was added at 0° C. The resulting mixture was stirred at RT for 2 h and subjected to the usual work up to obtain acetic acid 3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (1.4 g, 89%) which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH2:13]([N:15]([CH2:26][CH3:27])[CH2:16][CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:14]>C1COCC1.CC(O)C>[CH2:26]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[CH3:27]
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCN(CC)CCOc1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 1.89 g (10 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 100 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 100 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. The precipitate is collected, washed with 2-propanol, and dissolved in water. After being filtered through celite, the aqueous solution is basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried, to give 2.88 g (80%) of the title compound: mp (EtOH)163–164° C.
Reaction SMILES: O=O.[O:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6].CO.[H][H]>Cl.C(Cl)Cl>[OH:3][C@H:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)C(=O)C(C)(C)C
Reactant: [H][H]
Agent: Cl
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@H](O)C(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
A catalyst solution was prepared in a glove box (O2 content<1 ppm) by dissolving 385 mg (0.5 mmol) of [Ru(OAc)2((R)-BIPHEMP)] in 40 ml of a 0.025 molar methanolic hydrochloric acid solution and 40 ml of methylene chloride, subsequently stirred at 20° C. for 1.5 hours and thereafter transferred into a pressure-tight catalyst supply vessel. A 2 l steel autoclave was charged with 71.6 g (0.5 mol) of 2-keto-3,3,N-trimethyl-butyramide and 310 ml of methanol and sealed. After replacement of the atmosphere with hydrogen the catalyst solution was allowed to flow from the catalyst supply vessel into the autoclave with slight over-pressure and the hydrogenation was carried out while stirring at 60° C. and at a pressure of 60 bar (6 MPa). After 20 hours the hydrogenation was interrupted and the reaction mixture was evaporated. From a solution of the residue in 250 ml of diisopropyl ether there firstly separated at room temperature 1.2 g of crystalline product with ee=3% and a melting point of 135-137° C. By adding 275 ml of cyclohexane and stirring the mixture in an ice bath for 3 hours there were isolated 43.9 g (60.5%) of (R)-2-hydroxy-3,3,N-trimethyl-butyramide; m.p. 69-71° C.; [α]=+61.0° (c=1, CHCl3), ee=98.7% (measured by GC on an OV-61/p-DiMe-β-CD chiral column).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>O.CCO>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc2ccccc2c1
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium cyanide (10.5 g, 0.214 mol) in H2O (20 mL) was added a solution of 2-(bromomethyl)naphthalene (40.0 g, 0.181 mol) in EtOH (170 mL). The resulting mixture was heated at reflux for 3 h, then spin-evaporated in vacuo. The residue was partitioned between H2O (175 mL) and CH2Cl2 (200 mL). The aqueous layer was further extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over MgSO4 (5 g) and spin-evaporated in vacuo to a solid. The solid was dissolved in refluxing EtOH (100 mL). The clarified solution was stored at 3° C. for 16 h. Solids were collected by filtration and dried to constant weight in vacuo to give 24.8 g (81.9%) of product suitable for further transformation. A total of 257.2 g of material was prepared in this fashion.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3](OCC)=[O:4].[O-:31][C:32]#[N:33].[K+]>C(O)CCC>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:2]2[O:1][C:32](=[O:31])[NH:33][C:3]2=[O:4])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC2OC(=O)NC2=O)cc1
Yield: 62.7 %

Procedure:
A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (0.45 g), powdery potassium cyanate (0.24 g) and butanol (20 ml) was heated for 4 days under reflux. The solvent was distilled off under reduced pressure, and the residue was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3) was obtained 5-(2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]-2,4-oxazolidinedione (0.28 g, 63%). The product was recrystallized from dichloromethane-ethanol to give colorless prisms, m.p.193-194° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:36])[CH3:35])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000056 mol) and potassium carbonate (0.016 g, 0.00012 mol) in anhydrous N,N,-dimethylformamide (1 mL) was added acetic anhydride (0.009 g, 0.000084 mol) at room temperature. The reaction mixture was stirred for 1 hours. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 5 μm, 100×20 mm; 20%-85% over 7.5 min with 0.05 M ammonium acetate, 25 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetany}-1-ethanone (0.014 g, 0.000035 mol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH:26]=O)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][C:17]=2[CH2:26][NH:31][CH2:29][CH3:30])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: 2-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](Cl)=[N:7][CH:8]=1.[CH2:13]([OH:15])[CH3:14]>>[Br:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:15][CH2:13][CH3:14])=[N:7][CH:8]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [Na]
Product: CCOc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium (3.22 g) was dissolved in absolute ethanol (100 ml) and added dropwise to a suspension of 5-bromo-2-chloro-3-nitropyridine (30.2 g) in ethanol (100 ml) at 0° C. over 10 mins. The cold bath was removed and the reaction stirred at RT for 18 h. The reaction was evaporated to approximately half its volume then diluted with saturated ammonium chloride (aq) (600 ml). The reaction was stirred at RT overnight then the solids were filtered and rinsed well with water. The solids were dissolved in hot ethanol (100 ml) then diluted with hot water (500 ml) and stirred with cooling to RT for 2 hr. The solids were collected and rinsed well with water then suction dried and vacuum dried to give the title compound (26.4 g) as a dark brown solid.