Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[CH2:2].[Br-:11]>CN(C)C=O>[Br:11]/[CH:2]=[CH:1]/[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: [Br-]
Reactant: C=Cc1c[nH]c(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(/C=C/Br)c(=O)[nH]1
Yield: 83.4 %

Procedure:
5-vinyluracil (2.75 g, 20 mmoles) was dissolved in dry dimethylformamide (250 ml). To this solution was added a solution of bromide (3.2 g, 20 mmoles) in dry dimethylformamide (30 ml). The reaction mixture was shaken until colourless and then heated at 100° for 1 hour. The solution was then evaporated under reduced pressure to a brown oil to which was added water (30 ml). The resulting pink suspension was filtered and the pale pink solid recrystallised from methanol to give E-5-(2-bromovinyl)uracil (3.62 g, 84% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[NH:9])[NH:11][NH2:12])[N:3]=1
Reactant: NN
Reactant: Cc1ccnc(C#N)n1
Solvent: CCO
Solvent: O
Product: Cc1ccnc(C(=N)NN)n1

Procedure:
4-methyl-2-pyrimidinecarbonitrile (I98)(0.190 g, 1.595 mmol) was dissolved in ethanol (3.19 ml) and hydrazine hydrate (0.100 ml, 3.19 mmol) was added. The reaction mixture was left at reflux for 2.5 hours. TLC showed that no starting material remained so the solvent was removed under reduced pressure to afford the crude desired product in 247 mg.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH2:6]1)=O.[OH-].[Na+].C(Cl)(Cl)Cl>O.C1C=CC=CC=1>[CH2:4]1[CH:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[C:11]2=[C:12]([CH:13]=[CH:14][CH:15]=3)[CH:1]=[N:3]1
Reactant: O=CNCC1Cc2ccccc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C1=NCC2Cc3ccccc3Cc3cccc1c32
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
N-Formyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine (6.7 g, 0.027 mole), described in Example 334, in combined with polyphosphoric acid (50 g) and the mixture stirred for 3.5 hr. at 155° - 160° C. (bath temperature). The darkish reaction mixture is poured hot into stirred ice-water (400 ml). After stirring for 0.5 hr. (and treatment of the sticky precipitate with a glass rod) a solution of sodium hydroxide (60 g) in water is added, followed by chloroform. The chloroform solution is twice replaced by fresh chloroform and after 1 hr. the precipitate is almost dissolved. The combined chloroform solutions are washed with water, dried (Na2SO4) and taken to dryness to give a dark residue. The residue is dissolved in a little benzene and subjected to chromatography on neutral alumina (300 g). Elution with hexane-benzene (1:1) and benzene-ethyl acetate (9.5: 0.5) gives an oil which on crystallization from a concentrated ether solution gives 1,7,12,12a-tetrahydrobenzo[1,2]cyclohepta[4,5,6-de]isoquinoline, m.p. 91° - 93° C, γmaxCHCl3 1629, 1588, 1578, 1490 cm-1. The corresponding hydrochloride acid addition salt has m.p. 285° - 289° C, after recrystallization from chloroform-ether and methanol-ether.
Reaction SMILES: C(O[C:6](=[O:17])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C.[C:18](O)(C(F)(F)F)=O.C(Cl)Cl.C[C:29]1[C:30](C(O)=O)=[C:31]([C:34]([OH:36])=[O:35])[S:32][CH:33]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=N)C>CN(C=O)C>[CH3:18][O:36][C:34]([C:31]1[S:32][C:33]([C:6](=[O:17])[NH:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1csc(C(=O)O)c1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCNc1ccccn1
Agent: CCN=C=N
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCNc2ccccn2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of [2-(Pyridin-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (44 mg, 0.14 mmol) was mixed with a mixture of (1:1)TFA/CH2Cl2 (30 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was tritured with dry ether (2×30 mL). This gave 35 mg (95%) of pure trifluoroacetate salt. The salt was neutralized with DIEA and treated with mono methylthiophene dicarboxylic acid (32 mg, 0.17 mmol), hydroxybenzotriazole (24 mg, 0.17 mmol) in DMF (20 mL). To this mixture was added 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol). The reaction was stirred overnight at room temperature. Insolubles were removed by filtration and the solvent was evaporated. Purification of the residue on silica gel (5% MeOH/EtOAc) gave 38 mg (88%) of pure 5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester. 1HNMR (300 MHz, CDCl3) δ: 3.43 (m, 2H), 3.51 (m, 2H), 3.92 (s, 3H), 6.45(d, 1H) 6.80(t, 1H), 7.42(t, 1H), 7.45 (s, 1H), 7.55 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[C:10](=O)[N:9]([CH3:19])[CH2:8][C:7]=12)#[CH:2].C([Li])CCC.CN(C)P(=[O:34])(N(C)C)N(C)C.[CH3:36][C:37]([CH:39]1[CH2:41][CH2:40]1)=[O:38]>O1CCCC1.CCCCCC.O>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[C:5](=[O:34])[NH:4][C:3]([C:1]#[C:2][C:37]([CH:39]4[CH2:41][CH2:40]4)([OH:38])[CH3:36])=[C:7]3[CH2:8][N:9]([CH3:19])[CH2:10][C:11]=2[CH:16]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: CC(=O)C1CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2cc(F)ccc2-n2c(c(C#CC(C)(O)C3CC3)[nH]c2=O)C1
Reaction time: 2 h

Procedure:
2.55 g (10 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 20 ml of tetrahydrofuran and treated dropwise within 30 minutes at -5° with 13 ml (20 mmol) of 1.6M butyllithium in hexane. After stirring in an ice-bath for 2 hours the mixture was cooled to -70° and 3.4 ml of hexamethylphosphoric acid triamide and 1.68 g (20 mmol) of cyclopropyl methyl ketone were added thereto in succession. The mixture was left to come to room temperature within 4 hours, stirred overnight and poured into about 200 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate, the combined extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel while eluting with ethyl acetate and after crystallization from ethyl acetate there was obtained 8-fluoro-3-(3-cyclopropyl-3-hydroxy-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one of melting point 191°-192°.
Reaction SMILES: [C:1](=[O:38])([O:16][CH2:17]/[C:18](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[C:19](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[CH2:20][OH:21])[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:41].O>ClCCl>[N+:13]([O:12][CH:6]([CH2:7][O:8][N+:9]([O-:11])=[O:10])[CH2:5][CH2:4][CH2:3][O:2][C:1]([O:16][CH2:17]/[C:18](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=1)=[C:19](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[C:20]([OH:41])=[O:21])=[O:38])([O-:15])=[O:14]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.4 %

Procedure:
To a solution of 4.5 g of 4,5-bis(nitrooxy)pentyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 50 mL of dichloromethane, 4.13 g of Dess-Martin reagent was added and the resulted mixture was stirred at 25° C. for 45 min. Then 250 uL of water was added and the mixture was stirred at RT for 15 min. Then the mixture was filtered through a pad of silica gel and evaporated. The crude was dissolved in a mixture of THF and t-BuOH (25 mL/25 mL). To this solution was added 6.8 mL of 2-methyl-2-butene followed by the addition of 20 mL of phosphoric acid (1.2M soln) and 20 mL of NaClO2 (1M soln). The resulted mixture was stirred at RT for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography to afford 2.6 g of the titled compound as white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.44 (d, 2H), 7.17 (s, 3H), 7.12 (t, 2H), 5.51 (s, 1H), 5.35 (s, 2H), 5.00 (dd, 1H), 4.72 (dd, 1H), 4.13-4.10 (m, 2H), 3.06 (s, 3H), 1.87-1.80 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[BH4-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[OH:13]
Reactant: COc1cccc2c1CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CCCC2O

Procedure:
To a solution of 5-methoxy-3,4-dihydro-2H-naphthalen-1-one (CAS#33892-75-0, 10 g, 5.67 mmol) in methanol (40 mL) and dichloromethane (5 mL) at 0° C. is added sodium borohydride (0.579 g, 8.51 mmol) in one portion. The cooling bath is removed and after 1.5 hours, the mixture is poured into water (75 mL) and the volatile organics are removed in vacuo. Extraction with dichloromethane, drying over sodium sulfate, filtering through a cotton plug and concentration affords 5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: N[C:2]1([C:8]([OH:10])=O)[N:7]=[CH:6][CH:5]=[N:4][CH2:3]1.C([N:15](CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]2[N:47]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:46]3[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=3[N:44]=2)[CH2:38][CH2:37]1>ClCCl>[NH2:15][C:3]1[C:2]([C:8]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)[C:46]4[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=4[N:44]=3)[CH2:38][CH2:37]2)=[O:10])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: NC1(C(=O)O)CN=CC=N1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Product: Nc1nccnc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred mixture of 2.1 parts of 3-amino-3-pyrazinecarboxylic acid, 2.8 parts of N,N-dibutylbutanamine and 195 parts of dichloromethane were added 3.83 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 15 minutes at room temperature, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine were added and stirring was continued for one hour. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The latter was decanted and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 2.8 parts (38%) of 3-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamide; mp. 156.9° C. (compound 113).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][N:10]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:12]1[C:13](=[O:15])[NH:14][C:9](=[O:8])[NH:10][CH:11]=1
Reactant: c1ccc(COc2ncc(-c3cccs3)c(OCc3ccccc3)n2)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of 2,4-bis(benzyloxy)-5-(thiophen-2-yl)pyrimidine (Prep21, 20 g, 53.5 mol) in dry dichloromethane (400 ml), iodotrimethylsilane (28.8 g, 0.14 mol) was added at room temperature. The resulting solution was stirred for 3 hours. Then methanol was added, the precipitate was filtered and the solid was recrystallized with methanol twice, to afford 7 g of the title compound (y=67.3%)
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:29]=[CH:28][C:27]2[C:18](=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[CH:29]=[CH:28][C:27]2[C:18](=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1ccc2cc3ccccc3cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=COc1ccc2cc3ccccc3cc2c1
Yield: 56.5 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 1.203 parts of t-BuOK and 6.816 parts of THF and to this, a mixture of 10.000 parts of 2-propargyloxyanthracene and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed off by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 2-allenyloxy anthracene as colorless crystals (M.P. 90.3°-95.6° C).
Reaction SMILES: [CH:1](=[O:7])CCCCC.[CH:8](=O)[CH2:9]CCCCC.[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH3:18]>>[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH2:18][CH3:1].[CH2:16]([C:19]([CH2:20][OH:21])([CH:22]([OH:23])[OH:7])[CH3:24])[CH2:17][CH2:18][CH2:8][CH3:9]
Reactant: CCCCCC=O
Reactant: CCCC(CO)(CO)CO
Reactant: CCCCCCC=O
Product: CCCCC(CO)(CO)CO
Product: CCCCCC(C)(CO)C(O)O

Procedure:
2-n-Butyl-2-hydroxymethyl-propan-1,3-diol and 2-n-pentyl-2-hydroxymethyl-propan-3,3-diol were prepared from n-hexanal and n-heptanal respectively in a manner analogous to that described for the synthesis of 2-n-propyl-2-hydroxymethyl-propan-1,3-diol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([N:21]2[CH:29]([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.Cl[C:44]1[C:49]([F:50])=[C:48]([Cl:51])[N:47]=[CH:46][N:45]=1>O1CCCC1.C(OCC)(=O)C.O>[Cl:51][C:48]1[N:47]=[CH:46][N:45]=[C:44]([C:29]2([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22](=[O:42])[N:21]2[C@@H:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH3:20])[C:49]=1[F:50]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncnc(Cl)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Add sodium bis(trimethylsilyl)amide (210 mL, 210 mmol, 1 M THF) drop wise over 60 minutes to an ice cold suspension of 2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (62 g, 144 mmol) and 4,6-dichloro-5-fluoropyrimidine (31 g, 186 mmol) in tetrahydrofuran (620 mL). Stir the solution 60 minutes at 0° C. and then dilute the mixture with ethyl acetate (1 L) and water (1 L). Wash the organic phase with saturated aqueous sodium chloride and evaporate under reduced pressure. Dissolve the residue in 1:1 petroleum ether/ethyl acetate, filter through a pad of silica gel, and evaporate to give the title compound as a yellow foam (83 g, 103%). ES/MS m/z: 562 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:35]([O:37][C@H:38]1[CH2:42][CH2:41][O:40][CH2:39]1)=[O:36]>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:35](=[O:36])[O:37][C@H:38]3[CH2:42][CH2:41][O:40][CH2:39]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.57 mmol) in DMF under an N2 atmosphere at 0° C. was added triethylamine (115 mg, 1.14 mmol) followed by the dropwise addition of (S)-tetrahydrofuran-3-yl chloroformate (86 mg, 0.57 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was partitioned between H2O and CH2Cl2 and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 4:1 CH2Cl2:EtOAc afforded (S)-tetrahydrofuran-3-yl ((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate. LC/MS: m/z 463.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N+:11]([C:14]1[CH:15]=[C:16]2[C:21](=[O:22])OC(=O)[C:17]2=[CH:23][CH:24]=1)([O-:13])=[O:12].[C:25](O)(=O)C>>[N+:11]([C:14]1[CH:24]=[CH:23][CH:17]=[C:16]2[C:15]=1[CH2:25][N:1]([CH:2]([CH2:3][CH2:4][C:5](=[O:7])[NH2:6])[C:8]([OH:10])=[O:9])[C:21]2=[O:22])([O-:13])=[O:12]
Reactant: CC(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: NC(=O)CCC(C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O

Procedure:
A mixture of glutamine (10 mmol) and 4-nitrophthalic anhydride (10 mmol) in 15 mL of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue purified by chromatography to afford 2-(4-nitro-1-oxoisoindolin-2-yl)-4-carbamoylbutanoic acid.
Reaction SMILES: CO.[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10].[BH4-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([Cl:12])=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: O=Cc1cc(Br)cc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(Br)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:36][O:37][C:38](=[O:41])[CH2:39]Cl.O>CN(C=O)C>[CH3:36][O:37][C:38](=[O:41])[CH2:39][N:26]([CH3:27])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:28])=[O:29]
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(C)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.047 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.071 mmol) and chloro-acetic acid methyl ester (0.071 mmol). Stirred at 40° C. for 2 h and then added H2O (1.5 mL). Extracted with EtOAc (3×1 mL) and the combined organic phases were washed with brine (1 mL) and concentrated in vacuo. The residual oil was treated with TFA (1 mL) at rt for 1 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21].[NH4+].[Cl-]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. The 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an aqueous NH4Cl solution, and then washed with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The pentane solution was filtered over silica. The solution was concentrated to about 20% of the original volume and then the product was crystallized at -30° C. A yield of 10.88 g of 1-bromo-2-(fluorenyl)ethane was obtained. The product was characterized through
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8](=[O:10])[NH2:9])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl>O.O1CCCC1.C(OCC)(=O)C>[C:8]([CH2:7][CH2:6][C@H:2]([NH:1][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21])[C:3]([OH:5])=[O:4])(=[O:10])[NH2:9]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)CC[C@H](NC(=O)C1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-2-Amino-4-carbamoyl-butyric acid (100 mg, 0.684 mmol) in water (16 mL) are added Na2CO3 (218 mg, 2.052 mmol) and a solution of cyclopropylcarboxylic acid (62.1 uL, 0.684 mmol) in tetrahydrofuran (8 mL). After stirring at rt during 2 h, ethyl acetate is added and the pH is decreased to 3 by addition of aqueous 1N HCl. The aqueous phase is evaporated, the residue is mixed with methanol and filtrated. The filtrate is evaporated to yield the title compound.