Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[NH:12][CH:13]=[C:14]([CH3:20])[CH2:15][C:16]=1[C:17]([OH:19])=[O:18])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C>O1CCCC1.[Pd]>[CH2:1]([N:8]=[C:9]([CH:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][CH:14]([CH3:20])[CH2:13][NH:12]1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CNC(C(O)=NCc2ccccc2)=C(C(=O)O)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1CNC(C(O)=NCc2ccccc2)C(C(=O)O)C1

Procedure:
17.5 g (70 mmol) of 5-methyl-1,4-dihydropyridine-2,3-dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70° C. and under 100 bar over palladium on active charcoal. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The solid oily residue (13.0 g) is used as a crude product in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:17]=2[C:18]([NH2:19])=[N:31][C:30]([NH2:32])=[N:29]3)[CH2:12][CH2:13]1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCN(c2ccccc2Cl)CC1
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCN(c4ccccc4Cl)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
2-[1-(2-Chlorophenyl)piperidin-4-ylmethoxy]-6-fluorobenzonitrile (0.28 g; 0.81 mmol) and guanidine carbonate (0.293 mg; 1.6 mmol) were heated at 140° C. in dimethylacetamide for 2 days, then cooled back to room temperature. The reaction mixture was diluted with water, stirred for 45 minutes, filtered, triturated with ethanol, and filtered. Solids were dried to afford 90 milligrams of 5-[1-(2-chlorophenyl)-piperidin-4-ylmethoxy)quinazoline-2,4-diamine (29% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[N:8]=[C:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:10][CH:11]=1)[C:4]([OH:6])=[O:5].[CH3:32][O:33][C:34]([CH3:36])=[CH2:35]>C(Cl)Cl>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3](=[N:2][O:1][C:34]([CH3:36])([O:33][CH3:32])[CH3:35])[C:4]([OH:6])=[O:5])[N:8]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=C(C)OC
Solvent: ClCCl
Product: COC(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of the syn isomer of 2-hydroxyimino-2-(2-tritylamino-4-thiazolyl)-acetic acid, 120 ml of methylene chloride and 12 ml of 2-methoxy-propene was stirred at room temperature for 20 minutes and was evaporated to dryness. The residue was stirred with 60 ml of methylene chloride and 12 ml of 2-methoxy-propene for 30 minutes and the mixture was evaporated to dryness to obtain the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetic acid which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:24][CH:25]=3)[NH:18][CH:19]=2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]([CH3:7])[S:3]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[NH:18][CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[N:16]=3)=[CH:25][N:24]=2)[CH2:31][CH2:30]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(-c3nc(-c4ccc(F)cc4)c[nH]3)cn2)CC1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
N,N-Dimethylsulfamoyl chloride (0.09 g) was added to a solution of 1-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (0.2 g) and pyridine (0.05 g) in THF. The reaction mixture was held at room temperature overnight and then concentrated in vacuo. The residue was diluted with 1N NaOH and the resultant mixture extracted with dichloromethane. The organics were extracted with 6N HCl, and the acidic extracts basified with 1N NaOH. The basic aqueous layer was then extracted with dichloromethane. The organics were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography on silica (20% ethyl acetate in hexanes grading to ethyl acetate grading to dichloromethane) to provide 4-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine-1-sulfonic acid dimethylamide (0.11 g). MS m/z 431 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([C:22]([O:24][CH3:25])=[O:23])[O:10][CH:8]1[OH:9])(=[O:5])[CH3:4].[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]#[N:29]>ClCCl>[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]([O:9][C@H:8]1[O:10][C@H:11]([C:22]([O:24][CH3:25])=[O:23])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:7]1[O:6][C:3](=[O:5])[CH3:4])=[NH:29]
Reactant: COC(=O)[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Oily sodium hydride (0,366 g) was added to an ice-cooled solution of methyl 2,3,4-tri-O-acetyl-D-glucopyranuronate (3.96 g), trichloroacetonitrile (12 ml) and dichloromethane (100 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was subjected to short column (70φ×50 mm) chromatography on silica gel and eluted with ethyl acetate/hexane (1:1). The eluate was concentrated under reduced pressure to obtain the desired compound (4.37 g) as crystals (mp: 108° C.).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=1[O:24][CH3:25].O.NN>CO>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][C:13]=1[O:24][CH3:25]
Reactant: COc1cc(S(=O)(=O)N(C)C)ccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(S(=O)(=O)N(C)C)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
4-(1,3-Dioxoisoindolin-2-yl)-3-methoxy-N,N-dimethylbenzenesulfonamide (Preparation 105, 50 mg, 0.139 mmol) was suspended in MeOH (6 mL) and hydrazine hydrate (1 mL) was added. The resulting solution was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 50% EtOAc in cyclohexane to give the title compound as white solid (11 mg, 34%).
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[CH:9]1[C:17]2[C:16]3[C:18]([C:26]4[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=4)=[C:19]4[C:24](=[CH:25][C:15]=3[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH:23]=[CH:22][CH:21]=[CH:20]4.[Br:35]Br>C(Cl)Cl>[Br:35][C:25]1[C:15]2[S:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:17]=3[C:16]=2[C:18]([C:26]2[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Oc1c(F)ccc(-c2c3ccccc3cc3sc4ccccc4c23)c1F
Reactant: BrBr
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reaction time: 0.47 h

Procedure:
To a cold (-23° C. dry ice/carbon tetrachloride bath) stirred solution of 3-(benzo [b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (1.38 g, 3.81 mmol) in methylene chloride (35 mL) was added a solution of bromine (0.22 mL, 4.19 mmol) in methylene chloride (7 mL) dropwise, very slowly, over a period of 28 minutes. After stirring an additional 1.5 h the reaction was quenched with dilute sodium bisulfite and the organics were extracted with ether. The extract was concentrated to give a yellow solid (1.64 g, 98% crude yield). A small portion was taken up in methylene chloride and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (85/15 petroleum ether/ethyl acetate) to give the title compound as an off white solid: mp 180-182° C.; NMR (400 MHz, DMSO-d6); δ10.64 (s, 1 H), 8.30 (d, J=9 Hz, 1 H), 8.09 (d, J=9 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.64-7.51 (m, 3 H), 7.42-7.37 (m, 1 H), 7.33-7.29 (m, 1 H), 6.96-6.91 (m, 1 H), 6.81-6.78 (m, 1 H); MS (FAB): (M-H): one bromine pattern observed; 439/441 (8%); Anal. Calc. for C22H11BrF2OS: C, 59.88, H, 2.51, N, 0.00%. Found: C, 59.82, H, 2.59, N, 0.06.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][OH:13])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: OCn1ccc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
The mixture of 2.88 g of 3-phenyl-1H-pyrazole, 0.67 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. After the mixture was filtered, hexane was added to the filterate to produce a crystal. The crystal was collected to obtain 2.64 g of 3-phenyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[I:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1>N1CCCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:22]/[C:18]1[CH:17]=[C:16]2[C:21]([C:13]([I:12])=[N:14][N:15]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccc(F)cc43)cc21
Temperature: 55 °C
Yield: 77.1 %

Procedure:
A round bottom flask was charged with 5-fluoroindolin-2-one (100 mg, 0.661 mmol), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (266.18 mg, 0.661 mmol), piperidine (13 uL, 0.013 mmol) and methanol (7.5 mL). The reaction was then heated to 55° C. for 4 h prior to cooling the reaction mass to room temperature. Filtration and washing with methanol (0.50 mL×2) gave the title compound as a yellow solid (273 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.0, 2.4 Hz, 1H), 6.97 (td, J=6.4, 2.4 Hz, 1H), 6.85 (dd, J=8.4, 4.4 Hz, 1H), 5.80 (s, 2H), 3.58 (t, J=8.4 Hz, 2H), 0.92 (t, J=8.4 Hz, 2H), 0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17]C)=[CH:9][CH:10]=3)[C@:5]3([N:23]=[C:22]([NH2:24])[CH2:21][O:20][CH2:19]3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:24][C:22]1[CH2:21][O:20][CH2:19][C@:5]2([C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[C:14]([F:16])[C:13]=3[O:12][C:11]3[C:6]2=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[N:23]=1
Reactant: COc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cc(F)c1O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500-mL flask, the (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.595 g, 1.513 mmol) was dissolved in DCM (45 mL). The orange solution was cooled to 0° C. and a DCM solution of boron tribromide (1.0 M, 4.54 mL, 4.54 mmol) was added. After 2 h, the reaction mixture was quenched with 20 mL of 9:1 NH4Cl/NH4OH. The mixture was diluted further with water (10 mL) and the aqueous phase was extracted with 5% MeOH-dcm (3×60 mL). The organics were combined, washed with brine (20 mL), dried over sodium sulfate and concentrated to afford crude (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.574 g, 1.21 mmol) which was used directly in the next step.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[CH:13][C:9]=1[C:10](Cl)=[O:11].[CH3:20][N:21]([CH3:28])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:28])[CH:22]=[C:23]([C:10](=[O:11])[C:9]1[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:8]=1[F:7])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To dioxane (80 ml) solution of 2,3,4,5-tetrafluorobenzoyl chloride (21.25 g) was added dioxane (25 ml) solution of methyl 3-dimethylaminoacrylate (12.92 g) with ice-cooling, and triethylamine (14.46 ml) was added thereto with ice-cooling. The mixture was stirred for 30 minutes at the same temperature, then for 3 hours at room temperature, and then for one hour at 50° to 60° C. The mixture was concentrated under reduced pressure, then dissolved in methylene chloride (200 ml), washed with water (200 ml) and brine (100 ml) in order, then dried with sodium sulfate and concentrated under reduced pressure to obtain a syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed liquid of methanol/methylene chloride (3/97, V/V) to obtain methyl 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (15.47 g) as a syrup product.
Reaction SMILES: Cl[C:2]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:3].CN(C)CC[OH:25]>O1CCCC1>[C:2]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)([OH:25])=[O:3]
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccc2c(=O)c3cccc(Cl)c3ccc2c1
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(=O)c3cccc(Cl)c3ccc2c1
Reaction time: 16 h

Procedure:
1.0 G. of 2-chlorocarbonyl-9-chloro-5-oxo-5H-dibenzo[a,d]cycloheptene, as prepared in Example VIII, is dissolved in 10 ml. of anhydrous tetrahydrofuran with stirring, and treated with 2 ml. of dimethylethanolamine. After the solution is stirred for 16 hours, it is evaporated. The residue is partitioned between ether and dilute hydrochloric acid. The aqueous layer is basified with aqueous ammonia and extracted with ethyl acetate. This solution is evaporated and the residue chromatographed on silica gel, eluting with 10:90:1 methanol:chloroform:triethylamine, to afford the β-N,N-dimethylaminoethyl ester of 2-carboxy-9-chloro-5-oxo-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:31]([C:32]5[C:33]([CH3:47])=[N:34][N:35]([CH2:38][C:39]6[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=6)[C:36]=5[CH3:37])=[CH:30][N:29](C(OC(C)(C)C)=O)[C:23]4=[N:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:55]>CO>[ClH:55].[CH:26]1([C:25]2[N:24]=[C:23]3[NH:29][CH:30]=[C:31]([C:32]4[C:33]([CH3:47])=[N:34][N:35]([CH2:38][C:39]5[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=5)[C:36]=4[CH3:37])[C:22]3=[CH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[CH2:27][CH2:28]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2nc(C3CC3)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1c[nH]c2nc(C3CC3)c(-c3ccc(N4CCNCC4)cc3)cc12
Yield: 5 %

Procedure:
Using similar reaction conditions as described in Step-ii of example-7, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-6-cyclopropyl-3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (62 mg, 0.022 mmol) was deprotected in HCl in methanol (2 ml). This afforded 4 mg (5% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.44 (b, 1H), 7.68 (s, 1H), 7.42-7.39 (d, 2H), 7.02-7.00 (d, 2H), 6.661-6.641 (m, 1H), 6.311-6.305 (d, 1H), 5.26 (s, 2H), 3.25-3.21 (m, 3H), 3.10-3.07 (t, 3H), 2.41 (s, 3H), 2.32 (s, 3H), 1.13-1.10 (m, 2H), 0.88-0.85 (m, 4H). MS: m/z=539.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10]3(OCC[O:14]3)[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].CC(C)=O.Cl.C([O-])(O)=O.[Na+]>O>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10](=[O:14])[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
The title compound was prepared according to the procedure of Pelcman (W02006032851, 1996). A 250 mL flask, equipped with a magnetic stirbar and reflux condenser, was charged with 3′-nitro-7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline] (4.75 g, 20.1 mmol), acetone (65 mL), hydrochloric acid (2N (aq), 42 mL), and water (21 mL). The mixture was heated to 65° C. for 1 h, then to 80° C. for 30 minutes. The mixture was cooled to ambient temperature and neutralized with saturated NaHCO3 (aq) until pH=8. The mixture was extracted with EtOAc (3×) and the combined organic portions were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (30 to 60% EtOAc in hexanes) to afford the title compound (2.5 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CCN([CH2:16][CH3:17])CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:16][CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CCCCCC/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 181.8 %

Procedure:
1-bromo-4-nitrobenzene (2.01 g, 10 mmol), 1-ocetene (7.8 mL, 50 mmol), and Pd(OAc)2 (50 mg, 0.2 mmol) were stirred for 10 min under nitrogen atmosphere. Then tri-o-tolylphosphine (24 mg, 0.8 mmol) was added to the mixture and stirred for 10 min. Et3N (5.5 mL, 40 mmol) was then added to the mixture. The mixture was heated to 110° C. for 18 h. Water was added to the mixture and extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE as eluent to give compound the title compound (2.121 g, 90%). 1H NMR (300 MHz, CDCl3) δ 8.097 (d, 2H), 7.235 (d, 2H), 6.442 (s, 1H), 5.976-5.377 (m, 1H), 2.231-2.052 (m, 2H), 1.710-1.246(m, 8H), 0.850 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[H][H]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(C(O)CNC2CC2)cc(Br)c1N
Reactant: [H][H]
Solvent: CO
Product: N#Cc1cc(C(O)CNC2CC2)ccc1N

Procedure:
4 gm of 1-(4'-amino-3'-bromo-5'-cyano-phenyl)-2-cyclopropylamino-ethanol was dissolved in methanol, and the solution was hydrogenated at room temperature at a hydrogen pressure of 3 to 5 atmospheres after addition of 1 gm of palladized coal (10%). After termination of hydrogen absorption, the catalyst was suction-filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was distributed between dilute sodium hydroxide and chloroform. After evaporation of the chloroform phase, 1-(4'-amino-3'-cyano-phenyl)-2-cyclopropylamino-ethanol was obtained as an oil, which was purified chromatographically on silicagel (eluant: chloroform:methanol = 9:1). The dihydrochloride, obtained by addition of ethereal hydrochloric acid, was recrystallized from isopropanol. M.p. 148°-151° C. (decomp.).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3]O.[OH-].[Na+].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[C:9]1([S:15]([N:1]2[CH2:3][C@H:2]2[CH2:5][CH3:6])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC[C@@H](N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H]1CN1S(=O)(=O)c1ccccc1
Temperature: 62 °C
Yield: 70.7 %

Procedure:
Four grams of 2-(R)-aminobutanol and 7.2 grams of NaOH are suspended in toluene in a round bottom flask at ambient temperature. Benzenesulfonyl chloride (16.7 g) is added with agitation in one portion. The resulting white suspension is heated at 62° C. for 6 hours. Water (90 mL) is added and the layers are separated. The organic layer is washed with 70 ml of water, dried over magnesium sulfate and concentrated to provide 1-benzenesulfonyl-2(R)-ethylaziridine (6.7 g) as a colorless oil which is purified by flash chromatography over silica gel. MS: m/z (E1, 70EV) 212 (20%)
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=O.N1CCCCC1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 82.6 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (106 mg) (prepared as described in Compound IN-02), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL) was heated in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 140 mg (83% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: CCCCS
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1ccc(Br)cn1
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-2-chloro-pyridine (2.0 g), 1-butanethiol (1.3 mL), cesium carbonate (4.5 g) and DMF (5 mL) was heated to 60° C. for 3 hours. The mixture was diluted with water and extracted three times with EA. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to provide the subtitle compound. MS ESI+: m/z=246 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[C:37]=[O:39]
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCN)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCN=C=O)c2)n1
Reaction time: 0.5 h

Procedure:
Methyl 6-(3-(6-aminohexyloxy)phenyl)picolinate dihydrochloride (19) (40 mg, 0.10 mmol) and DIEA (34 μL, 26 mg, 0.20 mmol) were dissolved in CHCl3 (0.7 mL). Triphosgene (14 mg, 0.047 mmol) was dissolved in CHCl3 (0.3 mL). The solutions were combined and a second portion of DIEA (34 μL, 26 mg, 0.20 mmol) was immediately added. The mixture was left to stand 30 min at RT and evaporated. The residue was dissolved in ethyl acetate and the precipitated DIEA hydrochloride was filtered off. The solvent was evaporated and the crude isocyanate (20) was used directly for the next step.