Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:18])[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]4=[O:18])=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCOC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then acidifying with TFA and purification of the residue by chromatography (preparative HPLC).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].[OH-].[Na+].CO>C(O)C.O>[F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (5 g, 29.36 mmol) in ethanol (30 ml) was slowly added aqueous sodium hydroxide ((2.35 g, 58.72 mmol, dissolved in water (30 ml)), and stirred for 20 h at room temperature until the starting material was consumed. The reaction mixture was concentrated and the resulting white solid was dissolved in water (100 ml). The aqueous layer was extracted by ethyl acetate (50 ml×2), and then the aqueous layer was adjusted PH to 1˜2 with concentrated HCl, and concentrated to give a white solid. The solid was added to methanol (200 ml) and stirred for overnight, filtered, and the filtrate was concentrated and dried to give the crude product (4.13 g, 99%) as a white solid, used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([CH:12]1[CH2:14][CH2:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC.[Cl-].[NH4+]>[C:1]([O:5][C:6]([NH:8][S:9]([C:12]1([CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:14]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C(O)c2ccccc2)CC1
Temperature: -78 °C

Procedure:
Under inert gas, 1.00 g of N-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 1 hour. After stirring at room temperature for a further 30 minutes, the mixture was cooled again to −78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF was added. The mixture was allowed to come to room temperature while stirring overnight. The reaction solution was diluted with 20 ml of a saturated aqueous ammonium chloride solution and extracted with 40 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 mg) with a molecular weight of 327.4 g/mol (C15H21NO5S); MS (ESI): m/e=254 (M-tert-butanol+H+).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:50](OC(=O)C)(=[O:52])[CH3:51].C(N(CC)CC)C>ClCCl>[C:50]([NH:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:52])[CH3:51]
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNC(C)=O)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate dihydrochloride (230 mg/0.28 mmol), acetic anhydride (0.2 ml/2.1 mmol) and triethylamine (0.5 ml/3.5 mmol) in dichloromethane (5.0 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (50 ml), and then washed with water (10 ml) and brine (10 ml) successively. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/200-350 mesh/20 g/dichloromethane) to give a yellow film (110 mg/53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1C#N.[OH-:22].[Na+].COC[CH2:27][OH:28].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([C:27]([OH:28])=[O:22])[CH:9]=1
Reactant: [OH-]
Reactant: COCCO
Reactant: Cc1cc(C)c2ncc(C#N)c(-c3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2nc(C(=O)O)cc(-c3ccccc3Cl)c2c1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A mixture of 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarbonitrile (0.5 g), 6N-sodium hydroxide (1.5 ml) and 2-methoxyethanol (3 ml) was refluxed under stirring for 8 hrs. The mixture was diluted with water and acidified with hydrochloric acid. The resultant precipitate was collected by filtration to give 4-(2-chlorophenyl)-6,8-dimethyl-2-quinolinecarboxylic acid (0.46 g, 86.8%), which was recrystallized from ethanol to give colorless prisms. m.p. 234°-235° C. This substance was identical with that obtained in Reference Example 33.
Reaction SMILES: C1COCC1.C(O)(=O)C(O)=O.C[O:13][CH:14](OC)[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[CH2:20]([O:19][C:17]([NH:16][CH2:15][CH:14]=[O:13])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(CNC(=O)OCc1ccccc1)OC
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=CCNC(=O)OCc1ccccc1
Yield: 50 %

Procedure:
To a solution of 80 ml THF, 40 ml water, and 800 mg oxalic acid was added 9.6 g (40 mmol) of N-benzyloxycarbonyl aminoacetaldehyde dimethyl acetal, and refluxed for 4 days. The THF was removed under reduced pressure and the remaining solution was extracted with ether (3×100 ml), the ether fractions were combined and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the remaining solution was purified by flash chromatography (hexane and ethyl acetate 3:1 then 1:1) to yield 3.88 g, 50% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[C@@H:25]([C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CC(O)C>[C:1]([O:5][C:6]([NH:8][N:9]([CH2:24][CH:25]([OH:23])[CH:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccn2)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccc(-c2ccccn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 66 %

Procedure:
Into a 100 mL flask was placed (5) (1.0 g, 3.34 mmol), (6) (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane (2.78 g, 10.5 mmol, 3.16 equivalents), and 2-propanol (15 mL). The reaction was heated to reflux. After approximately 61 hours of refluxing, the heat was removed, and the mixture cooled to room temperature. To the cooled mixture was added water/ice (50 mL). To the aqueous mixture was added dichloromethane (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and then dried over sodium sulfate. The dried organic solution was filtered, and the filtrate was concentrated under reduced pressure, and then dried under high vacuum overnight. The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV) to give 1.24 g (66%) of (7) as a white solid. TLC Rf (hexane/ethyl acetate, 1:2)=0.45; NMR (CD3OD) δ 8.60 (d, 1H), 7.88 (m 4H), 7.50 (d, 2H), 7.36 (m, 1H), 7.25 (m, 4H), 7.18 (m, 1H), 3.93 (m, 2H), 3.70 (m, 2H), 3.0-2.6 (m, 4H), 1.33 (s, 9H), 1.30 (s, 9H); MS (M)+=563; HPLC tR 9.6 minutes.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:25]2[CH:26]=[CH:27][N:22]=[N:23][CH:24]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Nc1ccnnc1
Product: O=C(Nc1ccnnc1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-pyridazinamine (CAN 20744-39-2, 31.4 mg, 0.33 mmol) as starting materials; off white solid (60 mg, 47.8%). MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21](F)=[C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19]=1[CH3:43])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:19]=1[CH3:43])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (139 μl, 1.10 mmol) and triethylamine (153 μl, 1.10 mmol) were added to a dimethyl sulfoxide (5 ml) solution of ethyl 4-[(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)amino]butanoate (I-280) (279 mg, 0.732 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (170 mg, 49%) as a brown oily substance.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[CH:16]([NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24](C2C=CC=C(Br)C=2)[CH:23]=1)=[O:21])([CH3:18])[CH3:17]>>[CH:16]1([NH:19][C:20]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([C:7]#[C:8][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)[CH:2]=3)[CH:23]=2)=[O:21])[CH2:17][CH2:18]1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1ccccc1
Reactant: Brc1cccnc1
Product: O=C(NC1CC1)c1cn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of Step 5 of EXAMPLE 1, but substituting N-cyclopropyl-1-(3-ethynylphenyl)- 1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for phenylacetylene and 3-bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide, the title compound was obtained as a solid.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][NH2:2])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1ccc(CBr)cc1C(F)(F)F
Product: Cc1ccc(CON)cc1C(F)(F)F

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 4-methyl-3-(trifluoromethyl)benzyl bromide (JRD fluorochemicals). 13C-NMR (CDCl3) δ 136.4, 135.5, 132.1, 131.5, 129.0, 125.8, 124.5, 77.0, 19.1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[C:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)#[N:13].[CH3:21]C([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:6]1[C:7]([CH3:21])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)nn2ccnc2c1Nc1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
To a mixture of free based 8-bromo-6-chloroimidazo[1,2-b]pyridazine from Example 1, step 1b (100 mg, 0.35 mmol) in THF (1.0 ml) was added p-cyanoaniline (42 mg, 0.35 mmol) and a 1.0 M solution of KOt-Bu in THF (3.0 eq, 1.05 ml, 1.05 mmol). The mixture was allowed to heat at 50° C. for 1 hour. The solution was then concentrated in vacuo to dryness to provide 4-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)benzonitrile as a solid m/e 284 (MH+)
Reaction SMILES: N1([O:10][C:11](=O)[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:20][C:18]1[CH:19]=[C:14]([CH:13]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)[C:11]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:10])[CH:15]=[C:16]([CH3:21])[CH:17]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: Cc1cc(C)cc(C=C(C(=O)N2CCOCC2)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Yield: 95.8 %

Procedure:
To a suspension of 48 (116 mg, 0.2 mmol) in dichloromethane (5 mL) at room temperature was added morpholine (87 μL, 1 mmol). Solution became clear. After 10 min the mixture was treated with 10% citric acid (4 mL). The dichloromethane layer was dried (MgSO4) and directly loaded onto a column which was eluted with hexanes:ethyl acetate (2:3) to yield 50 (104 mg, 86%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.85 (s, 1H), 6.72 (s, 2H), 6.61 (s, 1H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.59 (bs, 8H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.13 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Solvent: C1CCOC1
Product: Cc1cc(Br)c2[nH]ccc2c1
Temperature: -65 °C
Yield: 52 %

Procedure:
3.3 g of 2-bromo-4-methyl-1-nitro-benzene (15 mmol) were dissolved in 200 ml THF and the solution was cooled to −65° C. Then 46 ml of a 1 molar solution of vinyl magnesium bromide in THF were added in a way, that the temperature of the reaction mixture stayed below −40° C. After 30 min at −40° C. the reaction was quenched with saturated ammonium chloride solution and was extracted with EtOAc. The combined organic phases were washed with brine and dried with magnesium sulfate. After filtration and evaporation of the solvent the crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 4:1). 1.68 g (52%) of 7-bromo-5-methyl-indole were isolated as brown liquid. 1H NMR (DMSO-d6, 300 MHz): δ 2.36 (s, 3H), 6.45 (m, 1H), 7.14 (s, 1H), 7.34 (m, 2H), 11.16 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:13]=1
Reactant: N#Cc1ccc(O)cc1C(F)(F)F
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1C(F)(F)F

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 4-hydroxy-2-(trifluoromethyl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.[O:24]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25]1.C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>C1COCC1>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][CH2:29][CH:26]5[CH2:27][CH2:28][O:24][CH2:25]5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Reactant: O=CC1CCOC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2sc(N3CCOc4ccc(NCC5CCOC5)cc43)nc2C1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of Example 12 (50 mg, 0.15 mmol), tetrahydrofuran-3-carboxaldehyde (30 mg, 0.15 mmol), phenylsilane (0.04 mL, 0.3 mmol) and dibutyltin dichloride (5 mg, 0.015 mmol) in THF (3 mL) was heated to 100° C. under microwave irradiation for 40 min. After cooling to r.t., the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organics were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude material was purified by prep HPLC to give the title compound as a yellow solid (14 mg, 22%). δH (CDCl3) 1.08 (6H, s), 1.56-1.71 (2H, m), 1.98-2.13 (1H; m), 2.35 (2H, s), 2.43-2.57 (1H, m), 2.68 (2H, s), 3.03 (1H, d, J 6.8 Hz), 3.52-3.59 (1H, m), 3.65-3.76 (1H, m), 3.78-3.91 (2H, m), 4.08-4.15 (2H, m), 4.16-4.22 (2H, m), 6.32 (1H, dd, J 8.7, 2.4 Hz), 6.73 (1H, d, J 8.7 Hz), 7.10 (1H, d, J 2.6 Hz). LCMS (ES+) 414 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[OH-].[Na+].[C:5](#[N:14])[C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1>C(O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[C:5](=[N:1][OH:2])[NH2:14])#[N:10]
Reactant: N#Cc1cccc(C#N)c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(C(N)=NO)c1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) was treated with 10 N NaOH (10 mL, 100 mmol). To this solution, isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL of ethanol was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 5.98 (bs, 2H), 7.59 (t, J=7.4 Hz, 1H), 8.06-8.0 (m, 2H), 9.89 (s, 1H) ppm; MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:23].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].[OH-].[Na+]>C(O)CC(C)C>[CH3:19][O:18][C:12]1[CH:13]=[C:14]2[C:15]([NH2:17])=[N:16][C:7]([N:1]3[CH2:6][CH2:5][N:4]([C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][CH2:2]3)=[N:8][C:9]2=[CH:10][C:11]=1[O:20][CH3:21].[ClH:23]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1ccco1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(1-Piperazinyl)-4-amino-6,7-dimethoxyquinazoline (57.8 g., 0.20 mole) was dissolved in 1000 ml. of chloroform and 30.2 g. (0.20 mole) of 2-furoyl chloride was added slowly at ambient temperature. When the addition was completed the resulting slurry was stirred for 15 minutes after which 1000 ml. of isoamyl alcohol was added. To the resulting mixture was then added sufficient 10% (w/w) aqueous sodium hyroxide solution to effect the solution of the solid material, about 200 ml. was ordinarily required, while maintaining the mixture at room temperature. The aqueous layer was separated and the organic phase was washed with 250 ml. of water. The organic layer was dried over anhydrous MgSO4, filtered and the filtrate cooled to 0° C. Anhydrous hydrogen chloride was passed through the solution at 0°-5° C. until the solution was acidic to moistened test paper (pH about 2-2.5), about 45 minutes was required for the addition. The chloroform was then evaporated at reduced pressure while warming gently to about 45° at 20-30 mm Hg. The vacuum was then released and the solution heated to about 100° C. to remove the last traces of chloroform. The mixture was then allowed to cool to room temperature. The product was recovered by filtration, washed with chloroform and dried in the vacuum oven at 50°-60° C. to afford 73.9 g. of needle-like crystals, M.P. 277°-279° C. (dec.) of the title polymorph.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Reactant: OB(O)c1ccccc1Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1c[nH]c2nc(-c3ccccc3Cl)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-chlorophenylboronic acid (296 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (142 mg, 59%).