Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37]>C1COCC1.CCOC(C)=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (492 mg, 0.97 mmol) in THF (1 ml) was treated with a solution of 2M methylamine in THF (7 ml, 14.4 mmol) and stirred at 40° C. in a sealed vessel for 75 minutes. The reaction mixture was allowed to cool to room temprature and dissolved in EtOAc (100 ml) which was washed with sat. NaHCO3 (100 ml) solution followed by brine. The organic extract was dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (337 mg, 95%).
Reaction SMILES: C1C2C(COC(=O)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:59])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[C:39](=[O:40])[CH:38]([CH2:41][CH2:42][CH:43]([OH:50])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:37]4[C:51]4[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=4)=[CH:32][CH:31]=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>CN(C)C=O>[OH:50][CH:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][CH2:41][CH:38]1[C:39](=[O:40])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:28](=[O:59])[CH2:27][CH2:26][CH2:25][CH2:24][NH2:17])=[CH:35][CH:34]=2)[CH:37]1[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1

Procedure:
570 mg (0.78 mmol) of product 8 and 0.8 ml of diethylamin are solved in 5 ml of DMF (dimethylformamid). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenchloride/methanol/conc. ammoniac 30:10:3) 220 mg (56%) of product 9 is obtained in form of an amorphic solid compound: C30H35N3O4 (501.63) MS (ESI+) 502.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CN(C=O)C>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[CH:20][CH:21]=1
Reactant: N#Cc1cccc(O)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107 %

Procedure:
To a mixture of 3-hydroxybenzonitrile (4.76 g, 0.04 mol), K2CO3 (16.6 g, 0.12 mol) and DMF (100 ml) under argon was added 4-chloromethylpyridine hydrochloride (6.56 g, 0.04 mol). The reaction mixture was stirred at room temperature for about two days, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The organic layer was washed with 2N aqueous NaOH (1×100 ml), brine, then was dried over MgSO4. The solvent was removed in vacuo to afford, as an amber solid, 9.0 g of 3-(4-pyridinylmethoxy)benzonitrile.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6].Cl>ClCCl.C(S)C>[CH:5]([C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6]
Reactant: COc1ccc(S(=O)(=O)c2c(C(C)C)cc3ccccn23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CC(C)c1cc2ccccn2c1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.7 g (0.050 mole) of aluminium chloride are suspended in 100 ml of dichloromethane and 25 ml of ethanethiol. This suspension is stirred and cooled to 0° C. while 2.5 g of 2-isopropyl 3-p-methoxyphenylsulfonyl indolizine in dichloromethane are added. The addition takes about 15 minutes. The reaction mixture is allowed to warm to room temperature and maintained there for 45 minutes. It is poured onto ice, then 5 ml of concentrated hydrochloric acid are added with stirring. The mixture is extracted with 2 fractions of ethyl ether and the ethereal extracts are pooled. They are washed with 3 fractions of 30 ml of a 10% aqueous solution of sodium bicarbonate and the aqueous phase is acidified.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C@:19]2([CH3:25])[CH2:23][O:22]C(=O)[NH:20]2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[OH-].[Li+].C(O)C.O>>[NH2:20][C@@:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4]3)[CH:10]=2)[CH:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: CC1(C)CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of (R)-4-(6-(4,4-dimethylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one and lithium hydroxide (45 mg, 0.0019 mol) in ethanol (1.1 mL, 0.019 mol) and water (0.37 mL, 0.021 mol) was heated to reflux for overnight. The crude product was partitioned between ethyl acetate and water and the ethyl acetate layer was concentrated and the crude was brought up in methanol and purified by HPLC. MS: m/z=311.2 [M-NH2]+
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CC3CCC(C2)O3)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CC3CCC(C2)O3)n1
Yield: 90.9 %

Procedure:
Reaction of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate (513 mg, 0.896 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 3 hrs, followed by treatment with aq. NH3 gave 385 mg (91% yield) of 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane: mp 221-223° C.; 1H NMR (CDCl3) δ7.90 (dd, J=8.4, 0.6 Hz, 1H), 7.51 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.47 (d, J=9.6 Hz, 2H), 4.33 (t, J=12.1 Hz, 2H), 4.05 (s, 3H), 3.86 (br s, 4H), 3.28 (dd, J=32.5, 12.3 Hz, 2H), 2.95 (br s, 4H), 1.98 (dd, J=8.3, 4.5 Hz, 2H), 1.80 (m, 2H).
Reaction SMILES: [H-].[Na+].[N:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[C:4]=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[C:17]([O:24][CH2:25][CH3:26])[CH:16]=1>C1COCC1>[C:9]([C:8]1[CH:7]=[C:6]([NH:3][C:4](=[O:5])[O:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][C:17]=2[O:24][CH2:25][CH3:26])[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: CCOc1cc(Br)ccc1CCO
Reactant: N#Cc1cccc(N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
NaH (346 mg, 8.7 mmol, 60% dispersion in oil) was added in one portion to a solution of 3-isocyanatobenzonitrile (567 mmol, 3.9 mmol) and 62E (960 mg, 3.9 mmol) in THF (40 mL) and the cooling bath was removed. After stirring for 2 h at ambient temperature 1.0 N citric acid (50 mL) was added and the mixture was extracted with diethyl ether. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (0% to 60% EtOAc in hexanes) to yield 62F (611 mg, 50%) as a pale, yellow solid. MS (ESI) m/z 411.0/413.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]([C:16]([O:18]CC)=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:10]1([C:9]2[CH:8]([C:16]([OH:18])=[O:17])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(c2ccccc2)=C1c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Ethyl 2,3-diphenyl-cycloprop-2-ene-1-carboxylate (1.75 g, 6.6 mol) and potassium hydroxide (1.79 g, 31.9 mmol) were dissolved in methanol (60 cm3) and heated to reflux for 5 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was partitioned between water (30 cm3) and ethyl acetate (30 cm3). The aqueous layer was separated and washed with ethyl acetate (2×30 cm3) before being acidified to pH=1 with dilute hydrochloric acid and extracted with dichloromethane (3×40 cm3). The combined dichloromethane extracts were dried (MgSO4) and evaporated to give the cyclopropene acid 1.22 g, 78%.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[C:1]1([S:7][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(C(=O)CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of thiophenol (5.5 g) and 2-bromo-1-(4-(methanesulfonyl)phenyl)ethanone (14.8 g) in acetone (250 mL) was added K2CO3 (13.8 g). The mixture was stirred at r.t. for 1 hr then H2O added and the solution was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in EtOAc/Et2O, filtered and air dried, giving 13.4 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[C:7]([CH:19]=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-bromopyridine(5.13 g, 3.2 mmol) in THF (90 ml) at −78° C. was slowly added lithium diisopropylamide (LDA) (2 M in THF, 17.9 ml, 3.6 mmol) and the resulting reaction mixture allowed to stir for three hours. To the reaction mixture was then slowly added DMF (9.49 g, 130 mmol) in THF (10 ml). The reaction mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature. Water (100 mol) was added and then the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4. The solvent was removed and the resulting residue purified over silica gel chromatography eluted with hexane, to yield 2-bromo-pyridine-3-carbaldehyde as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:27]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:39]3[CH2:40][CH2:41][N:36]([C:27]4[C:26]([Cl:25])=[CH:31][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:29][N:28]=4)[CH2:37][CH2:38]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-[3-chloro-5-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as an off-white solid. MS: 600.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:24])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N+:19]([O-:40])([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Solvent: CO
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (22.2 mg, 0.05 mmol) in DCM (10 mL) and MeOH (1 mL) was added MCPBA (11.2 mg, 0.07 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, the combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was purified by RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-1-ethylpiperidine-1-oxide; 1HNMR (MeOD-d4) δ7.91 (s, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 3.28 (m, 4H), 2.91 (m, 1H), 2.32 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.83 (s, 2H), 1.64 (d, 2H), 1.31 (t, 3H); ESMS m/z 460.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:14][C:12](=[O:13])[C:3]2[N:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[N:1]=1)[CH3:16]
Reactant: CCSc1ccccc1C=O
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[C:20]([CH2:32][Cl:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][OH:24])[C:20]([CH2:32][Cl:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Solvent: O
Solvent: CC(=O)O
Product: OCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A 500 mL round bottom flask was charged with 7-(benzyloxy)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (30 g, 0.06 mol), acetic acid (300 mL), and water (60 mL). The suspension was heated at 50° C. for 24 hours. The heat was removed and the greenish homogeneous solution was concentrated to dryness. The solid was stirred in diethyl ether (300 mL) for 1 hour, isolated by vacuum filtration, washed with diethyl ether (100 mL), and dried on vacuum funnel to provide 23 g of 2-[7-(benzyloxy)-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol as a green solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1)=[O:6]
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)CCCBr)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Bromobutyryl chloride (29.4 mg, 0.158 mmol) was added to a solution of 8-(aminomethyl)-10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (61 mg, 0.132 mmol) and triethylamine (0.022 mL, 0.158 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 3.5 hours, then diluted with DCM (30 ml) and washed with saturated NaHCO3(aq) (30 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5](C(Cl)(Cl)Cl)[O:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]2[CH2:24][C@@H:19]1[CH2:20][NH:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]2[CH2:24][C@@H:19]1[CH2:20][N:21]2[C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Reactant: Cc1noc(C(Cl)(Cl)Cl)n1
Solvent: Cc1ccccc1
Product: Cc1noc(N2C[C@H]3C[C@@H]2CN3C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.2 %

Procedure:
A solution of 1.06 g of 3-methyl-5-trichloromethyl-1,2,4-oxadiazole prepared by the procedure of F. Eloy, Bull. Soc. Chim. Belg., 1964, 73, 793, in 2 ml of toluene is added slowly to a solution of 1.05 g of product from Example 1 and 0.82 g of diazabicyclo[3.6.0]unodecene-5 in 1 ml of toluene. The resulting mixture is stirred at room temperature for 3 days and then concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride) to give 0.74 g of the desired product as an off-white solid:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:24][C:21]1[N:20]=[CH:19][C:18]([C:8]2[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[CH:7]=2)=[CH:4][CH:3]=[C:2]([N:1]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:14]=4)=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)cn1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)cn1
Temperature: 200 °C

Procedure:
7-Amino-3-(6-methylpyridin-3-yl)-9H-carbazole-1-carboxamide (134 mg, 0.284 mmol), 1-chloro-2-(2-chloroethoxy)ethane (101 mg, 0.709 mmol) and Na2CO3 (180 mg, 1.703 mmol) were mixed with DMF (4 mL) in a sealed microwave vial. The mixture was heated in microwave at 200° C. for 2 hrs. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 387.00 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.16 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.3 (s, 1H), 8.18 (s, 1H), 8.15 (dd, 1H, J=8.0, 2.5), 8.05 (d, 1H, J=8.5), 7.51 (s, 1H), 7.37 (d, 1H, J=8.2), 7.24 (s, 1H), 6.94 (d, 1H, J=8.6), 3.8 (m, 4H), 3.19 (m, 4H), 2.53(s, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:17]#[N:18])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:17]#[N:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C#N)c2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cc(C#N)c2[nH]1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in MeOH (10 mL) was added NiCl2.6H2O (1.8 g, 7.2 mmol) at −5° C. The reaction mixture was stirred for 30 min, then NaBH4 (0.48 g, 14.32 mmol) was added to the reaction mixture at 0° C. After 5 min, the reaction mixture was quenched with water, filtered and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (5-20% EtOAc in petroleum ether) to obtain 5-amino-2-tert-butyl-1H-indol-7-carbonitrile (470 mg, 32% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 7.06 (d, J=2.4 Hz, 1 H), 6.84 (d, J=2.4 Hz, 1 H), 6.14 (d, J=2.4 Hz, 1 H), 3.57 (br s, 2 H), 1.38 (s, 9 H). MS (ESI) m/z: 214 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[CH3:17][O:18][CH2:19][C:20](O)=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH2:19][O:18][CH3:17])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: COCC(=O)O
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (1.00 g, 3.56 mmol) in DMF (5 mL) was introduced methoxyacetic acid (320 mg, 3.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (750 mg, 3.91 mmol), 1-hydroxy-7-azabenzotriazole (533 mg, 3.91 mmol) and triethylamine (720 mg, 7.11 mmol). The reaction mixture was stirred for 18 hr at RT and concentrated in vacuo. The residue was suspended in water (100 mL) and the resulting precipitate collected by filtration. After washing the filter cake with EtOAc (10 mL) and methanol (10 mL), the crude amide was dried on the filter. The intermediate amide was dissolved in glacial acetic acid (20 mL) and warmed to 140° C. for 15 minutes (microwave heating in 4 batches of equal volume). Following concentration of the reaction mixture in vacuo, toluene (20 mL) was introduced and the suspension concentrated in vacuo (repeated twice) to furnish the crude title compound as a brown oil: LC-MS: m/z=+334.90/336.75 (M+H)+. This compound, with LC-MS purity=86% UV, was used in the next step without further purification.