Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:16][Si:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:18][CH2:19]2)[C@@H:12]1[OH:34].[C:35]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[O:16][Si:17]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]
Reactant: O=C([O-])[O-]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a suspension of (6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol (300 mg, 0.57 mmol) and Cs2CO3 (1.86 g, 5.7 mmol) in DMF (5.7 mL) at 0° C. was added MeI (350 μL, 5.7 mmol) dropwise. The suspension was stirred for 3 hours, quenched with saturated aqueous NH4Cl and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 20% EtOAc/hexanes) to afford 221 mg (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]([CH:9]=1)=[N:19][N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]=2[NH2:7]
Reactant: NNc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c2ccc(Br)cc2nn1-c1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (4.0 g, 18.0 mmol) in n-butanol (60 mL) was added a solution of phenylhydrazine hydrochloride (10.4 g, 72.0 mmol, 4.0 eq) and diisopropylethylamine (13.2 mL, 75.6 mmol, 4.2 eq) in n-butanol (35 mL). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 10 to 65% EtOAc/hexane) and the product containing fractions were concentrated. Crystallization from DCM-hexane afforded 1.33 g (26%) of the title compound as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, 1H), 7.69 to 7.66 (m, 2H), 7.58 to 7.54 (m, 2H), 7.47 to 7.44 (m, 2H), 6.78 (dd, 1H), 6.50 (s, 2H); ES-MS m/z 288.1/290.1 [M+H]+, RT (min) 2.28.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.CS(O)(=O)=O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:24]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(C(C)=O)cc3CC12
Reaction time: 1 h

Procedure:
A mixture of (±) (1S,9aS/1R,9aR) N-[(9,9a-dihydro-3-oxo-1H,3H-oxazolo[3, 4-a]indol-1-yl)methyl]acetamide (X diastereomer B, EXAMPLE 11, 8 mg), methane sulfonic acid (0.5 ml), and acetic anhydride (10 μl) is stirred in methylene chloride (0.2 ml) from 0° to 20° for 19.5 hours. After this time the mixture is cooled in an ice bath and additional acetic anhydride (10 μl) is added. The mixture is stirred for one hour then added to a small amount of ice and saturated aqueous sodium bicarbonate (7 ml) is added, then solid sodium bicarbonate is added until alkaline. The mixture is then extracted with methylene chloride (5×, 20 ml total). The combined extract layers provide 8 mg of material. The 8 mg is then purified by chromatography (5 cm×0.5 cm disposable pipet, 40-63μ silica) eluting with 1% and 2.5% methanol/methylene chloride gradient while collecting 0.4 ml fractions. The appropriate fractions are pooled and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH:12](C)[CH3:13])[N:3]=1.CSC1N=C(NCC)N=C(NCC)N=1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=[C:6]([NH:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: CCNc1nc(NCC)nc(SC)n1
Product: CCNc1nc(Cl)nc(NCC)n1

Procedure:
2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine; 2-methylthio-4,6-bis-ethylamino-1,3,5-triazine; etc.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(OC(C)C)OC(C)C)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>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>[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:13]=2[NH:12][C:4]2[C:5]([CH3:11])=[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=2)[NH:9][CH:8]=[CH:7]3)[C:19]#[N:20])=[CH:28][CH:27]=1
Reactant: CC(C)OB(OC(C)C)c1ccc(OCCCl)cc1
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Temperature: 80 °C
Yield: 84.8 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (534 mg, 1.3 mmol) in DME (30 mL) was added diisopropyl 4-(2-chloroethoxy)phenylboronate (754 mg, 2.6 mmol), sodium carbonate solution (2.7 mL of 2M solution, 5.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.15 mmol) under nitrogen atmosphere and the reaction mixture was heated at 80° C. for 6 h and cooled to room temperature. Ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a yellow solid (482 mg, 84%). HPLC retention time: 10.7 min.(g) and MS: 437.2 (M+H).
Reaction SMILES: [C:1](=[O:11])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:2][CH3:3].[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1.C(=O)(OC)OC>CO>[C:1](=[O:11])([O:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Oc1ccccc1
Reactant: Oc1ccccc1
Solvent: CO
Solvent: COC(=O)OC
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a column apparatus as described in Example 15, in which, instead of the 10-tray sieve-plate column, a 10-tray bubble-cap tray column, isothermically thermostatted to 183° C., of length 72 cm and internal diameter 4.75 cm was used, there was reacted, under the conditions described there, a mixture of 150 g/h of methyl phenyl carbonate, 350 g/h of phenol and 6.25 g/h of octylstannonic acid. After establishment of constant conditions, at the head of the apparatus, 365 g/h of a mixture of 1.3% by weight of methanol, 8.5% by weight of dimethyl carbonate and 90.2% by weight of phenol was continuously withdrawn and, at the foot of the column, 135 g/h of a mixture of 6.2% by weight of phenol, 14.0% by weight of methyl phenyl carbonate and 79.8% by weight of diphenyl carbonate were continuously withdrawn. This represents a space-time yield for the formation of diphenyl carbonate of 0.085 g·ml-1· h-1, based on the reactor volume. 16.6% of the methyl phenyl carbonate used reacted with phenol with transesterification to form diphenyl carbonate. The selectivity of the formation of diphenyl carbonate was >99%, that is no by-products could be detected.
Reaction SMILES: C1CCN2C(=[N:5]CCC2)CC1.[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25](S(C)(=O)=O)[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].O>CN(C=O)C>[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25]([NH2:5])[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(N)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (0.204 ml, 1.354 mmol) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (232 mg, 0.451 mmol) and ammonium acetate (348 mg, 4.51 mmol) in DMF (2 ml), and the mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA. The combined fractions was concentrated, dissolved in MeOH, neutralized with NH4OH, concentrated, redissolved in MeOH, filtered through silica gel pad, washed with DCM:MeOH:NH4OH(10:1:0.1) and dried to give title compound. LC-MS: calculated for C24H27ClN4OSi 450.16 observed m/e: 451.13 (M+H)+ (Rt 1.25/2 min).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[CH2:6][C:5]=2[N:19]=1
Reactant: CC(=O)C1C(=O)CC(c2ccccc2F)CC1=O
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1F)C2

Procedure:
The title compound was prepared from 2-acetyl-5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (200 mg, 0.81 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: CN(C)CCN
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCN(C)C)CCCC2=O
Yield: 79.7 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and N1,N1-dimethylethane-1,2-diamine 0.19 g (2.1 mmol) was reacted to give 0.21 g (80%) of the titled compound as a white solid.
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][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H]1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
(S)-6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (30 mg) was dissolved in dichloromethane (1 ml) to prepare a solution. Trifluoroacetic acid (1 ml) was added dropwise to the solution at 0° C. The mixture was then stirred at room temperature for 3 hr. The reaction solution was made alkaline by the addition of a saturated aqueous sodium hydrogencarbonate solution and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 76%).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[CH2:2].[O:22]1[C:26](=O)[CH2:25][NH:24]C1=O.Cl.N>C(Cl)Cl.O>[ClH:21].[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24][CH2:25][C:26]1=[O:22])=[CH2:2]
Reactant: O=C1CNC(=O)O1
Reactant: C=COCCNc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: C=COCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
To a solution of 0.3g of 2-(β-vinyloxyethyl)amino-5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.27g of oxazolidin-2,5-dione. To the mixture is added 20 ml of etheral hydrogen chloride under cooling. The mixture is allowed to stand at room temperature with occasional stirring. The reaction mixture is poured into water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is dissolved in ether and treated with ethanolic hydrogen chloride to give 1-(β-vinyloxyethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride, m.p. 213° - 215° C (dec). Recrystallization from isopropanolchloroform gives colorless prisms, m.p. 216° - 218° C (dec.).
Reaction SMILES: [C:1]([C:3]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH:5]([N:7]([CH3:16])C(=O)OCC(Cl)(Cl)Cl)[CH3:6])#[N:2].C(O)=O>O1CCCC1.[Zn]>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:3]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:4][CH:5]([CH3:6])[N:7]([CH3:16])[C:1]2=[NH:2])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(C(C#N)(CC(C)N(C)C(=O)OCC(Cl)(Cl)Cl)c2ccccc2)c1
Agent: [Zn]
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=N)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product of Step 3 (40 g) was dissolved in tetrahydrofuran (500 mL). The solution was cooled to 0° C. using ice bath and stirred under Argon for 30 min. Then, 60 g zinc dust followed by 60 mL of formic acid (90%) was added to the reaction mixtures and stirring continued at 0° C. for 3 hr under argon purging. The stifling was continued at 25° C. for 16 hr under argon purging. Then, the reaction mixture was filtered and concentrated under vacuum. Crude Step 4 product was carried forward without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.Cl.Cl.[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]([CH3:28])[CH:14]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:24][CH2:23]2)=[C:15]([CH3:28])[CH:14]=1
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)c1ccc(OCCN2CCNCC2)c(C)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(OCCN2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
3,3-Dimethylbutyraldehyde (54 mg, 0.53 mmol) was added to a solution of 3-methyl-4-(2-piperazin-1-yl-ethoxy)-benzoic acid methyl ester dihydrochloride from Example E40.2 (146 mg, 0.42 mmol) in methanol/acetic acid (99:1, v/v, 10 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (42 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (64 mg, 34%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([C:20]([NH:22]C(=O)OCC)=S)[OH:19])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([O-])(=[O:30])C>>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([OH:19])[C:20]([NH2:22])=[O:30])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:4])[CH3:3]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)NC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(O)C(N)=O

Procedure:
[[[1-[3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]hydroxyamino]-thioxomethyl]carbamic acid, ethyl ester, acetate;
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(O)[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[CH2:4]
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1ccc(OC)cc1)C(F)(F)F

Procedure:
9.0 g of 1,1,1-trifluoro-2-(4-methoxyphenyl)-2-propanol were heated with 0.4 g of p-toluenesulfonic acid hydrate in 30 ml of glacial acetic acid until the elimination of water had ended. The reaction solution was concentrated, the residue was taken up in water, neutralised with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Distillation of the residue under reduced pressure (5.1×10−1 torr) gave the title product as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:20]=[CH:19][C:18]2OC3C(=CC=CC=3)NC=2C=1.[NH2:21][CH2:22]CC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:20][CH2:19][CH2:18][N:21]1[CH3:22]
Reactant: c1ccc(-c2ccc3c(c2)Nc2ccccc2O3)nc1
Reactant: CN1CCCC1CCN
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCCC1c1ccccn1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
2-Pyridinyl phenoxazine (28 mg,), 2-(2-aminoethyl)-1-methylpyrrolidine (17 ul, 0.1173 mmol) and aluminum chloride (21 mg, 0.1575 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrrolidine (17.5 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].II.C(OCC)(=O)C>O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Agent: II
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 40 °C
Yield: 70 %

Procedure:
Into a reactor, equipped with a mechanic stirrer and a reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (120 g;0.609 moles), sodium nitrite (96.6 g; 1.4 moles), iodine (31.2 g; 0.123 moles) and ethyl acetate (720 ml) were charged at room temperature and under inert gas. The mixture was heated under stirring at 40° C., then Oxistrong 15® (173.4 g) was added in 4 hours. At the end of the addition the reaction mixture was kept under stirring for 1 hour, then cooled at 20° C. Water (480 ml) was added and the mixture was kept under stirring for 1 hour. After filtration and wash of the panel with isopropyl acetate pre-cooled at 0° C. (2×120 ml) and then with water (150 ml), the solid was dried in oven under vacuum at 50° C. overnight obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (112.7 g; titre 91%; 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[N:27]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[N:27]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)n2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)nc(Cl)n3)CC1)C(=O)N2

Procedure:
275 mg (1.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 324 mg (1.00 mmol) 6-(2,6-dichloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.00 mmol) DIPEA in 5.00 mL DMF were stirred overnight at RT. Then the mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution and the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:20])=[O:19]
Reactant: OCCc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccncc1

Procedure:
The 4-(2-hydroxyethyl)pyridine (Lancaster, 0.153 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.