Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH:10]([OH:11])[O:9][CH2:8][CH:7]1[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][CH:10]1[O:9][CH2:8][CH:7]2[C:2]1([CH3:1])[CH:3]1[CH2:12][CH:6]2[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC12C3CCC(C3)C1COC2O
Solvent: c1ccncc1
Product: CC(=O)OC1OCC2C3CCC(C3)C12C
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 63 g of 2-methyl-4-oxatricyclo[5.2.1.02,6]decan-3-ol, 42 g of pyridine, and 51 g of acetic anhydride was heated at 50° C. for 5 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 74 g (yield 96%) of the target compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[CH3:12][C:13]#[N:14]>CC1C=CC=C([Sn](CCCC)(CCCC)CCCC)N=1.C(OCC)C.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:11][C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[CH:2][CH:3]=[C:4]([CH3:5])[N:14]=2)[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]=12
Reactant: Clc1cc(Br)nc2[nH]ccc12
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Solvent: CCOCC
Product: Cc1cccc(-c2cc(Cl)c3cc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1 eq, 11.0 mmol, 2.76 g) in MeCN (20 ml), 2-methyl-6-tributylstannanyl-pyridine (see Chemistry, A European Journal (2005), 11 (23), 6818-6828) (1 eq, 11.0 mmol, 4.19 g) and Pd(PPh3)4 (0.01 eq, 0.110 mmol, 131 mg) are added. The resulting mixture is heated using microwave radiation for 15 min at 160° C. The mixture is diluted with diethyl ether and extracted with aqueous HCl solution (2 M). The aqueous layer is basified with aqueous NaOH solution (4 M) and extracted with DCM. The organic layer is dried with MgSO4, filtered, and concentrated. The residue is taken up in hexane and stirred at r.t. for 1 h. The suspension is filtered and dried giving the title compound; [M+H]+=244.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:18]#[N:19])[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[NH2:19][C:18]1[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:8]=[N:9][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: CCCCNC(=O)C(C#N)=NNc1ccccc1Br
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 26.1 %

Procedure:
To a solution of 2-[(2-bromophenyl)-hydrazono]-N-butyl-2-cyanoacetamide (2.5 g, 7.7 mmol) in anhydrous toluene (Aldrich, 50 mL) under N2 was added portion-wise aluminum chloride (Aldrich, 3.1 g, 23.2 mmol) over 5 minutes. The mixture was heated to 90° C. with vigorous stirring for 1.5 hours then cooled to ˜0° C. Water (3 mL) was added dropwise followed by careful addition of Rochelle's salt (saturated aqueous potassium sodium tartrate, 50 mL). The reaction was stirred for 25 minutes and then poured into a separatory funnel. The aqueous layer contained a thick white precipitate and was quickly removed. The organic layer was washed with Rochelle's salt and brine, dried over magnesium sulfate, filtered and concentrated to give 2.6 g slightly crude product which was purified on silica gel using a gradient of 20 to 60% ethyl acetate in hexane. Recrystallization from ethyl acetate/hexanes (10mL each, 0° C. overnight) afforded the title compound as a white solid (650 mg, 26%). 1H NMR (300.132 MHz, CDCl3) δ 8.55 (bs, 1H), 8.13 (dd, J=7.4, 1.0 Hz, 1H), 7.82 (dd, J=8.5, 1.0 Hz, 1H), 7.50 (dd, J=8.5, 7.6 Hz, 1H), 3.52 (q, J=6.6 Hz, 2H), 1.65 (quintet, J=7.2 Hz, 2H), 1.47 (sextet, J=7.3 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H). MS APCI, m/z=323/325 (M+H). HPLC 1.93 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1CC1(NS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), methane-sulfonyl chloride (0.31 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 (2 mL) is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>C1COCC1.O>[Cl:27][CH2:28][C:29]([NH:14][C:12]1[S:13][C:9]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Compound 186 (0.900 g, 2.42 mmol) was dissolved in THF (10 mL), and N,N-dimethylaminopyridine (29.6 mg, 0.242 mmol), triethylamine (0.740 mL, 5.32 mmol) and chloroacetyl chloride (0.390 mL, 4.84 mmol) were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. Further, triethylamine (0.740 mL, 5.32 mmol) and chloroacetyl chloride (0.390 mL, 4.84 mmol) were added to the reaction mixture under ice-cooling, followed by stirring for 1 hour at room temperature. Water and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=2:1) to afford the entitled Compound 262 (0.810 g, 96%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1cc(N)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-methylisoxazol-3-amine (1.0 g, 10.2 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.09 g, 15.3 mmol), Pd2(dba)3 (467 mg, 0.51 mmol), Xantphos (598 mg, 1.02 mmol), Cs2CO3 (6.65 g, 20.4 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was filtered when the mixture was still hot. The filtrate was cooled down to room temperature and the resulting precipitation was collected by filtration to afford 283a (1.6 g, 55%) as a yellow solid. MS-ESI: [M+H]+ 284.1
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[OH:13].CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:38][C:37]1[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:42])[F:43])=[CH:41][CH:40]=1)=[C:5]2[OH:13]
Reactant: Oc1cc(O)c2cc(I)ccc2n1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CCO
Solvent: c1ccncc1
Product: Oc1nc2ccc(I)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-iodoquinoline-2,4-diol (498.2 g, 1.736 mol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (439.6 g, 1.736 mol) in pyridine (3.5 L) was added 4-(trifluoromethyl)benzaldehyde (332.4 g, 1.909 mol). The resulting mixture was warmed with stirring to 105° C. for a period of 6 h. After cooling to room temperature, the heterogeneous mixture was treated with ethanol (4.6 L). White solids were isolated through filtration, washed with 57:43 ethanol:pyridine (800 mL), and dried in a vacuum oven at 65° C. The title compound was obtained in a 1:0.92 ratio with pyridine and used directly in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: ClCCCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCCCCl)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
To a round-bottom flask was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50 mmol), 1-bromo-3-chloropropane (9.88 mL, 100 mmol), potassium carbonate (20.7 g, 150 mmol), and acetonitrile (100 mL). The reaction mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and was filtered. The filtrate was concentrated to give crude 2-[4-(3-chloro-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. This material was used for next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH3:28]>C(#N)C.O>[CH3:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: C[C@@H]1CCCN1CCCCl
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.55 g) in acetonitrile (10 mL), cesium carbonate (2.0 g) and (2R)-1-(3-chloropropyl)-2-methylpyrrolidine prepared in Example 1-(1) (0.50 g) were added and stirred at 100° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1). The resulting solid was subjected to recrystallization from n-hexane to give the titled compound (0.33 g, 37%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[NH2:26][CH2:25][CH2:24][NH:27][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: NCCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCN)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (100 mg, 0.26 mmol, 1.00 equiv) in DCM (5 mL). This was followed by the addition of a solution of ethane-1,2-diamine (307 mg, 5.11 mmol, 19.96 equiv) in DCM/DMF (10/1 mL). The resulting solution was stirred for 5 h at room temperature. The mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl acetate and washed with 2×10 mL of water and then 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 90 mg (76%) of N-(2-aminoethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10]>>[CH3:7][N:8]([CH3:13])[S:9]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C1NCCN1
Product: CN(C)S(=O)(=O)N1CCNC1=O

Procedure:
The starting material required for the above reaction is prepared as follows: A mixture of 17.2g of ethylene urea and 28.7 g of N,N-dimethyl sulphamoyl chloride is heated at 110° for 3 hours. The reaction mixture is cooled and triturated with 100 ml methanol. Some solid material separated which is discarded. The filtrate is evaporated off to dryness and the residue is dissolved in 5% methanol in chloroform and chromatographed on a column of 150 g of silica gel. The fraction which eluted with 2% methanol in chloroform is recrystallised from a mixture of methylenechloride and hexane to give 1-(N,N-dimethylsulphamoyl)-2-oxo-tetrahydroimidazole which melts at 129°.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30](=[O:38])[N:31]([CH2:35][CH2:36][NH2:37])[CH2:32][CH2:33][F:34])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30](=[O:38])[N:31]([CH2:35][CH2:36][NH:37][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22])[CH2:32][CH2:33][F:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(CCN)CCF
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN(CCF)C(=O)OC(C)(C)C)ccc21
Yield: 65.6 %

Procedure:
(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (70 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (2-amino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (90 mg), HBTU (100 mg), and DIEA (70 uL) in DMF (1.5 mL).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9 L) was added EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306, 2.14 equiv) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv) and the solution was stirred for 20 minutes at room temperature. Then it was cooled to 15-20° C. and cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv) was added and stirred at room temperature. The reaction was monitored by TLC. After 14 hours, since the reaction was not complete and additional cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirring was continued for two hours. DMF was removed under reduced pressure at 50-55° C. To the residue EtOAc (1 L) and water (500 ml) were added and the mixture was stirred for 10 minutes. The mixture was extracted and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layer was washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue EtOAc/dichloromethane/hexane (50 ml/50 ml/50 ml) was added, the mixture was stirred for 10 minutes, and filtered to provide the product (34.1 g, 65.7%) as an off white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 50/50, 30 min elution) tR 5.53 min, 99.3% purity; MS m/z 360 [M]+; 1H NMR (DMSO-d6, 400 MHz) is consistent with Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([C:32]([NH2:34])=[O:33])[C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[C:22]([C:28](O)([CH3:30])[CH3:29])[CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([C:32]([NH2:34])=[O:33])[C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[C:22]([C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)([CH3:30])[CH3:29])[CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(CN4CCOCC4)c(Cl)c3)cc12
Agent: Cl
Solvent: ClCCl
Product: CC(C)(c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(CN4CCOCC4)c(Cl)c3)cc12)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
3-(3-Chloro-4-(morpholinomethyl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (40.3 mg, 0.080 mmol, Example 399) was suspended in HCl (1 M solution in diethyl ether) (5 ml, 5.00 mmol) and sonicated briefly. (not completely dissolved. DCM was added (5 ml) in an unsuccessful attempt to dissolve more). The suspension was stirred at room temperature for 1 hour, then cooled to 0° C. Morpholine (5 ml, 57 4 mmol) was added, the ice bath removed and the mixture stirred at room temperature for 3 days. The reaction mixture was poured into a separating funnel that is loaded with EtOAc and sat. aq. NaHCO3 solution. Layers were separated, the aqueous extracted once more with EtOAc and the organic layer washed with brine, then dried over MgSO4, filtered and evaporated. The crude was purified by prep HPLC. Product containing fractions were filtered through a Waters MCX cartridge (1 g adsorbent), washed with MeOH and the product eluted with a 2M solution of NH3 in MeOH. Evaporation to dryness under a stream of nitrogen gave 10.8 mg white 3-(3-chloro-4-(morpholinomethyl)phenyl)-7-(2-morpholinopropan-2-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e−=545, m/e+=547 consistent with [M−H]− and [M+H]+. HPLC retention time 5.60 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.50 (d, 1H, J=1.7), 8.17 (d, 1H, J=1.5), 8.12 (d, 1H, J=8.3), 7.87 (d, 1H, J=1.7), 7.80 (d, 1H, J=0.7), 7.74 (dd, 1H, J=8.0, 1.8), 7.61 (d, 1H, J=8.1), 7.52 (dd, 1H, J=8.2, 1.6), 3.75-3.68 (m, 10H), 2.61-2.54 (m, 8H), 1.49 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)Cl.CCOCC>[Br:18][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:9]
Reactant: BrBr
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(Br)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a suspension of 30 g (0.12 mole) of 2-phenyl-1-(4-methylthiophenyl)ethanone in 45 ml of methylene chloride and 450 ml of ether was added dropwise a solution of 20.8 g (0.13 mole) of bromine in 65 ml of methylene chloride. The reaction mixture decolorized and became slightly exothermic. After stirring an additional 30 minutes, the reaction mixture was concentrated under vacuum. The crystalline product was collected by filtration and washed with hexane to give 36.3 g (91.5%) of 2-bromo-2-phenyl-1-(4-methylthiophenyl)ethanone as an off-white solid, m.p. 101°-103°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29].O>N1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1F
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cccc([C@@H](C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
A suspension of 4-{[(1R)-1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (2.0 g, 6.51 mmol) in dry pyridine (50 mL) was treated with 3-fluoro-4-methoxybenzoyl chloride (1.51 g, 8.01 mmol, 1.23 eq), and the contents were stirred at room temp for 45 min. The clear-yellow solution was slowly added to water (1000 mL), and the white precipitate was filtered, washed with water (300 mL) and dried under vacuum at 35° C. to get the title compound in 98% yield (2.93 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([O:14][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(C)C(O)CC=C(C)C
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6 mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washes with 5% sodium bicarbonate solution (2×100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.