Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.C1([SH:18])C=CC=CC=1.CCN(C(C)C)C(C)C.C[C:29]1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)O[C:31]2[C:32](P(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:33][CH:34]=[CH:35][C:30]1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([S:18][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: Sc1ccccc1
Reactant: COc1ccc(I)nc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(SCc2ccccc2)nc1OC
Reaction time: 2 h
Yield: 765.3 %

Procedure:
To a solution of 6-iodo-2,3-dimethoxypyridine (0.3 g, 1.13 mmol) in toluene (10 ml) was added phenyl mercaptan (0.21 g, 1.7 mmol) and DIPEA (0.32 g, 2.5 mmol). The reaction mass was degassed before Pd2(dba)3 (0.04 g, 0.05 mmol) and Xantphos (0.05 g, 0.1 mmol) were added and the whole was subjected to microwave irradiation at 120° C. with stirring for 2 hours. The resulting mixture was filtered through a pad of celite and the filtrate was added to water (60 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were dried (Na2SO4) and then concentrated. The crude product was purified by column chromatography (SiO2; 0-5% ethyl acetate/petrol) and product fractions concentrated to yield 6-(benzylsulfanyl)-2,3-dimethoxypyridine (0.2 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]([C:20]([CH3:26])([CH3:25])[C:21]([O:23]C)=O)=[C:17](O)[N:18]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:36]>C(#N)C>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]3[C:20]([CH3:26])([CH3:25])[C:21](=[O:23])[NH:36][C:17]=3[N:18]=2)=[N:6]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
48 mg (0.06 mmol, purity 54%) of methyl 2-{3-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 0.5 ml (5.36 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 10 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 5 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 8 h. The reaction mixture was concentrated on a rotary evaporator and the residue was partitioned between dichloromethane/water. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 4.5 mg of the target compound were obtained (18% of theory).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C#N)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-iodobenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>C1C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:37])/[CH:17]=[CH:11]/[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][CH:6]=1)[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/c1c[nH]c2ccc(C)cc12
Temperature: 80 °C
Yield: 95 %

Procedure:
5-methyl-1H-indole-3-carbaldehyde (900 mg, 5.65 mmol) was dissolved in benzene (100 ml), and ethyl(Triphenylphosphoranylidene)acetate (2954.1 mg, 8.48 ml) was drop-wise added. The temperature of mixture was raised to 80° C. and stirred under reflux for 12 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and refined through silica gel chromatography (n-hexane:EtOAc=4:1) to give target compound (1230 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=[O:9])=[O:4].COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.CC1CCCCC1>CC(C)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:7][C@@H:6]1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CC1CCCCC1
Solvent: CC(C)=O
Product: COC(=O)[C@H]1C[C@@H]1C(=O)O

Procedure:
Add trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester, Example 3a, (19.46 g) in acetone to quinine (43.8 g) in one portion. Heat the reaction to reflux, and then add methylcyclohexane (150 mL). After crystallization (5 times) from acetone/methylcyclohexane, collect 6.2 g of the diastereomeric salt (αD:+173, c:7.3 CHCl3)
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C=O)=[C:3]1C1C=CC=CC=1.C(CC(OC)=O)#N.N1CCCCC1>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1c(-c2ccccc2)c(C=O)c2ccccc21
Agent: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 263.8 %

Procedure:
To 120 ml of methanol were added 23.5 g (0.10 mol) of 1-methyl-2-phenyl-1H-indole-3-carbaldehyde and 11.9 g (0.12 mol) of methyl cyanoacetate to produce a mixture. Subsequently, 2.5 g (0.03 mol) of piperidine was added to the mixture, reacted under reflux for 6 hours, and cooled to room temperature to precipitate a crystal. The obtained crystal was washed with a small amount of methanol, and then dried to give 30.9 g of a light-yellow crystalline indole compound A having a structure of the general Chemical Formula (1) in which R1 was methyl group and R2 was methyl group. The melting point of the obtained indole compound A was 193.7° C.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]([CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:6].C([O:19][C:20](=O)[CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)C>C1(C)C=CC=CC=1.ClCCCl>[CH2:15]([N:7]([CH2:5][CH3:6])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:20](=[O:19])[CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH3:16]
Reactant: CCOC(=O)C(c1ccccc1)c1ccncc1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CCN(CC)c1ccc(NC(=O)C(c2ccccc2)c2ccncc2)cc1
Temperature: 60 °C
Yield: 32.7 %

Procedure:
Trimethylaluminum (2.0 mL of a 2.0 M solution in toluene, 4.0 mmol, 3.0 equiv) was added to a solution of N,N-diethyl-1,4-phenylenediamine (0.68 mL, 4.0 mmol, 3.0 equiv) in 1,2-dichloroethane (10 mL). The resultant solution was stirred at 23° C. for 30 minutes, and then phenyl-pyridin-4-yl-acetic acid ethyl ester (330 mg, 1.36 mmol, 1.0 equiv) was added. The reaction mixture was heated to 60° C. for 19 hours, cooled to 23° C., and quenched with 1 N aqueous tartaric acid. The pH of the reaction mixture was adjusted to 5, and the reaction mixture was extracted with three portions of ethyl acetate (50 mL). The combined organic extracts were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography (20% THF/hexanes grading to 100% THF) provided N-(4-Diethylamino-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide (160 mg). MS: 360 (M+1)
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: Oc1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.4 g), 4-hydroxyphenethyl bromide (0.32 g), sodium bicarbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 4 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.267 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37])=[O:6]
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Chlorobenzoyl chloride (61 mg, 0.35 mmol) and triethyl-amine (to pH9) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (101 mg, 69%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:12]([N:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCCCC)C(=O)c1ccccc1C(=O)O

Procedure:
Reaction of phthalic anhydride and arachidyl amine to form N,N-diarachidyl phthalamic acid.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1>O1CCCC1.C(OCC)C>[CH3:1][Si:2]([CH3:7])([C:3]([CH3:6])([CH3:5])[CH3:4])[O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Reaction time: 3 h

Procedure:
A solution of dimethyl-t-butylsilyl chloride (18 g.) in tetrahydrofuran (50 ml.) was added dropwise to a stirred solution of 8-bromooctanol (20 g.) and imidazole (14.2 g.) in tetrahydrofuran (100 ml.) and the mixture was stirred at laboratory temperature for 3 hours, diluted with diethyl ether (200 ml.) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using petroleum ether (b.p. 60-80° C.) as eluent. A solution of the 8-(dimethyl-t-butylsilyloxy)octyl bromide thus obtained (6.46 g.) in dimethyl sulphoxide (2 ml.) was added to a stirred suspension of lithium acetylide-ethylenediamine complex (2.02 g.) in dimethylsulphoxide (30 ml.) which was cooled to 10° C., and the mixture was stirred for 18 hours and then poured into ice-water (150 ml.). The mixture was extracted three times with petroleum ether (b.p. 60-80° C.; 30 ml. each time) and the combined extracts were washed with water (10 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 5:1 v/v mixture of cyclohexane and diethyl ether as eluent. There was thus obtained 10-(dimethyl-t-butylsilyloxy)dec-1-yne.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1([C:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OCC)(=O)C>C(#N)C>[S:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:28]([N:22]2[CH2:23][CH2:24][N:25]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:26][CH2:27]2)=[N:29]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(N)ccn1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2nc3ccccc3nc2Cl)ccn1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.14 g, 13.83 mmol) in dichloromethane (30.19 mL) was added dropwise to a mixture of methyl 4-aminopyridine-2-carboxylate (2.10 g, 13.83 mmol), pyridine (3.36 mL, 41.49 mmol) and dichloromethane (43.49 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature for 2 hrs. To the reaction, water (100 mL) was added and a precipitate formed. The solid was isolated by filtration, washed with water (1×40 mL) and hexanes (2×50 mL), then with 10 ml EtOAc and 10 ml dichloromethane and dried to yield methyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.64 g, 55%) as a blue-colored solid (1.54 g). ESI-MS m/z calc. 342.05, found 343.2 (M+1)+; Retention time: 0.95 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.34-8.27 (m, 1H), 8.24-8.16 (m, 1H), 8.13-8.00 (m, 2H), 7.94 (dd, J=5.4, 2.2 Hz, 1H), 3.91 (s, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].F[C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>>[CH3:1][CH:2]([CH3:5])[CH2:3][O:4][C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[CH3:16][C:9]1[CH:10]=[CH:11][C:12]([NH2:13])=[C:7]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])[CH:8]=1
Reactant: CC(C)CO
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc(N)c(OCC(C)C)c1
Product: Cc1ccc([N+](=O)[O-])c(OCC(C)C)c1

Procedure:
3-(2-Methylpropoxy)-4-nitrotoluene (0.78 g) is prepared from 2-methylpropanol (0.46 ml, 5.0 mmol) and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure G. This is reduced to afford 4-methyl-2-(2-methylpropoxy)aniline (0.47 g) following general procedure C. N-[4-Methyl-2-(2-methylpropoxy)phenyl]-N′-(thiazol-2-yl)urea (210 mg) is prepared from 4-methyl-2-(2-methylpropoxy)aniline (179 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccccc1
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Yield: 38 %

Procedure:
A solution of Compound 18 (5 g, 12.80 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.51 g (38%) of yellow solids. M.P. 219° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 5.54 (s, 2H), 7.23–7.26 (m, 3H), 7.29–7.32 (m, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.61 (dd, J=1.5, 8.8 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H). EIMS m/z 309 (M+1), 331 (M+23).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(N)Cc1ccc(F)cc1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)Cc1ccc(F)cc1
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.09 g, 0.508 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 1-2% MeOH/CH2Cl2 to provide the desired compound as a white powder. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.03 (4H, m).
Reaction SMILES: [C:1]12([CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][OH:12])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:12][CH2:11][CH:10]([NH:13][C:14]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23])[CH2:9][C:1]12[CH2:2][CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH2:8]2)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC(CO)CC12CCC(CC1)CC2)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 132.4 %

Procedure:
To a solution of benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-hydroxypropan-2-ylcarbamate (668 mg, 2.1 mmol, 1 eq.), TEA (638 mg, 6.3 mmol, 3 eq.) in CH2Cl2 (100 mL) was added dropwise MsCl (289 mg, 2.52 mmol, 1.2 eq.) at 0-5° C. The resulting mixture was stirred for 2 hrs. Then the mixture was poured into water (20 mL) and extracted with CH2Cl2 (20 mL×4). The organic phase was combined and evaporated to give 2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propyl methanesulfonate (1.1 g, crude) as oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Br:37][CH2:38][CH2:39]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C=O)C>[Br:37][CH2:38][CH2:39][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)=[CH:3][C:2]=1[Cl:1]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A 100 ml round bottom flask was loaded with 3-(3-chloro-4-hydroxyphenyl)-7-morpholino-9H-carbazole-1-carboxamide (114.9 mg, 0.245 mmol, Example 406), K2CO3 (386 mg, 2.79 mmol), DMF (10 ml) and 1,2-dibromoethane (0.24 ml, 2.79 mmol) and the mixture stirred at room temperature for 4 hours. The reaction mixture was partitioned between 500 ml water+citric acid (0.5 M solution in water) (20 ml, 10.00 mmol) and ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 118.6 mg 3-(4-(2-bromoethoxy)-3-chlorophenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=528/530/532, m/e−=526/528/530 consistent with isotope pattern for 1 Br and 1 Cl. 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.50 (d, 1H, J=1.5), 8.34 (b, 1H), 8.15 (d, 1H, J=1.6), 8.07 (d, 1H, J=8.5), 8.01 (d, 1H, J=2.2), 7.83 (dd, 1H, J=8.6, 2.4), 7.52 (b, 1H), 7.31 (d, 1H, J=8.8), 7.24 (d, 1H, J=2.0), 6.95 (dd, 1H, J=8.8, 2.2), 4.50 (t, 2H, J=5.5),), 3.89 (t, 2H, J=5.5), 3.83-3.79 (m, 4H), 3.22-3.17 (m, 4H).