Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][N:10]([CH3:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:17])[CH3:9])[CH2:12][CH2:13]2)[CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: Fc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C1CCN(c2cc(Br)ccn2)CC1
Temperature: 100 °C
Yield: 96 %

Procedure:
In a pressure vessel were dissolved 4-bromo-2-fluoropyridine (1 g, 5.68 mmol) and N,N-dimethylpiperidin-4-amine (1.1 g, 8.58 mmol) in DMSO (7 ml). Potassium carbonate (2.4 g, 17.36 mmol) was added and the reaction was heated at 100° C. overnight. The reaction mixture was poured into water and extracted twice with diethylether. The organics were combined, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.55 g (91% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:45])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:45][CH2:43][CH3:44])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethylamine (2.0 mol/L THF solution, 60.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-ethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.6 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[Li]CCCC.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[OH:27][C:24]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: CN(C)CCn1ccc2ccc(Br)cc21
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCn1ccc2ccc(C3(O)CCOCC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a solution of compound (ii), above, (380 mg, 1.4 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1 mL, 1.6 M sol. in hexane, 1.6 mmol). The mixture was stirred at −78° C. for 20 min. Tetrahydro-4H-pyran-4-one (280 mg, 2.8 mmol) dissolved in THF (1 mL) was added and the reaction mixture stirred at −78° C. for 2 hrs. The mixture was then quenched with NH4Cl (saturated) and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a yellow solid (150 mg, 37% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[NH:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccccc3)C(C)(C)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)NC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of 3-benzyl-1-(4′-methoxybenzyl)-2,5-dioxo-4,4-dimethylimidazolidine (3.9 g, 11.54 mmol) in acetonitrile (100 mL) was treated with a solution of ammonium cerium nitrate (31 g, 57.7 mmol) in 65 mL of water, stirred at 25° C. for 15 minutes, then diluted with ethyl acetate and partitioned between ethyl acetate and brine. The organic layer was dried, filtered, and concentrated. Purification by recrystalization with ethyl acetate/hexane provided 1.58 g (7.25 mmol, 63%) of the desired product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:34]C.B(Br)(Br)Br.C(Cl)Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:26])([F:25])[F:27])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[OH:34]
Reactant: COc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1c(-c2ccccc2)c2cc(O)c(Cl)cc2oc1=O)Nc1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A solution of 2-(7-chloro-6-methoxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (Example 178) (3.20 g) in methylene chloride (10 ml) was combined with a 1 M solution of boron tribromide/methylene chloride (31.6 ml, 13.6 mmol), and stirred at room temperature for 3 days. The reaction solution was poured into an ice water, to which concentrated hydrochloric acid was then added. The precipitate was filtered and washed with isopropanol followed by ether to obtain the title compound as a colorless crystal (2.05 g, 64%). An aliquot was recrystallized from THF-isopropyl ether to measure a melting point. Melting point: 246-247° C.
Reaction SMILES: C[O:2][C:3](=[O:51])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[N:52]([C@@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])=[C:53]=[O:54]>C(Cl)Cl>[CH:45]1([CH2:44][O:43][C:40]2[CH:41]=[CH:42][C:37]([C@H:35]3[CH2:34][O:33][C:29]4=[CH:30][C:31]5[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]6[CH:7]=[CH:8][C:9]([C:12]7[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=7[CH3:19])=[CH:10][CH:11]=6)[C:3]([OH:2])=[O:51])=[O:22])[N:24]([C:53](=[O:54])[NH:52][C@@H:55]([C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=6)[CH3:56])[CH2:25][C:26]=5[CH:27]=[C:28]4[O:36]3)=[CH:38][CH:39]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester in DCM was added ((R)-1-isocyanato-ethyl)-benzene (5 eq.) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 824.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:6]=1.[CH3:14][OH:15]>>[O:15]=[C:14]1[N:6]2[C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3][C:2]2=[N:1][CH:4]=[C:5]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(N)=N1
Reactant: CO
Product: COC(=O)c1cnc2n(c1=O)[C@H](C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of dimethyl methoxymethylene malonate (8.68 g, 49.8 mmol) in 100 mL MeOH at −10° C., was added a solution of 1e (8.50 g, 46.1 mmol) in 100 mL MeOH over 1 h. The mixture was stirred at rt for 2 h, then was allowed to warm to rt overnight. The mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (50 to 100% EtOAc/hexanes) to afford 6.32 g (46%) of pyrimidinone 1f, as a colorless solid. 1H NMR (300 MHz, CDCl3) δ8.69 (s, 1H), 5.03 (dd, J=9.7, 2.8, 1H), 3.90 (s, 3H), 3.38-3.09 (m, 2H), 2.64-2.49 (m, 1H), 2.34-2.23 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[C:24]([CH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[CH:33]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32]2)([OH:26])=[O:25].COC1C=CC(C=O)=CC=1>C(O)C>[OH:38][C@@H:34]1[C:35]2[C:31](=[CH:30][C:29]([CH2:28][CH2:27][C:24]([OH:26])=[O:25])=[CH:37][CH:36]=2)[CH2:32][C@H:33]1[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)C1Cc2cc(CCC(=O)O)ccc2C1=O
Agent: COc1ccc(C=O)cc1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CCOC(=O)[C@@H]1Cc2cc(CCC(=O)O)ccc2[C@H]1O
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Twenty grams of bakers' yeast (Sigma Chemical Company, type II) are suspended in an aqueous solution containing 30 grams of sucrose in a conical flask, and the mixture is placed on an orbital shaker (220 rpm) at 30° C. for 30 minutes to initiate fermentation. Two grams of 5-carboxyethyl-2-carboethoxy-1-indanone is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the fermenting yeast, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.5 grams of (1S,2R)-1-hydroxy-2-carboethoxy-5-carboxyethylindane as a yellowish oil (>95% enantiomeric excess as judged by chiral chromatography).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[N:26]=[C:25]2[C:33]([N:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])=[O:12])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[N:26]=[C:25]2[C:33]([N:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43]1)=[O:34])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCC(=O)OCc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 ml of 4N HCl in dioxane are added to 1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzyl 2-tert-butoxycarbonylaminoacetate in 50 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off and rinsed with 5 ml of dichloromethane.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:24]([N:31]1[CH:40]=[C:39]([C:41]([NH:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36](Br)[CH:37]=2)[C:32]1=[O:50])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[CH2:24]([N:31]1[CH:40]=[C:39]([C:41]([NH:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:10]3[CH:11]=[C:6]([C:5](=[O:23])[NH:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[C:8]([F:22])[C:9]=3[CH3:21])[CH:37]=2)[C:32]1=[O:50])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCNC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)NCCN(C)C)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a degassed mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.1 g) [prepared as described in WO 06110173], the product of step ii) (0.09 g) and potassium carbonate (0.06 g) in DMF (5 mL) under nitrogen, was added tetrakis(triphenylphosphine)palladium(0) (0.02 g) and the mixture stirred at 80° C. for 16 hours. The reaction mixture was concentrated to dryness and the crude product was purified (SiO2, elution with 90:10:0.1 dichloromethane: methanol: triethylamine) and by HPLC. The fractions containing product were concentrated to dryness and the residue crystallised from acetonitrile to afford the title compound as a solid (0.04 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[S:11][CH:12]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine (0.13 g, 0.50 mmol), triethylamine (0.10 mL, 0.75 mmol), and CH2Cl2 (1.7 mL) was cooled in an ice bath, and isobutyl chloroformate (0.10 mL, 0.75 mmol) was added. The reaction was stirred at 0° C. for 20 min, diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate. LC/MS: m/z 364.1 (M+H)+ at 3.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C1([NH:4][S:5]([NH2:8])(=[O:7])=[O:6])CC1.[CH:9]1[N:13]=[C:12]([NH2:14])[S:11][CH:10]=1>>[S:11]1[CH:10]=[CH:9][N:13]=[C:12]1[NH:14][NH:4][S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)NC1CC1
Reactant: Nc1nccs1
Product: NS(=O)(=O)NNc1nccs1

Procedure:
The titled compound was prepared according to the same procedures described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropyl amine with 2-amino thiozol. However, the Boc-protected intermediate was never isolated due to loss of the protection group during reaction work-up and the following recrystallization steps. The titled product was isolated after silica gel column chromatography (Biotage 40 M, eluent=5-10% MeOH in DCM). 1H NMR (d6-DMSO, 400 MHz)  6.52 (br s, 2H), 6.75 (d, 1H), 7.19 (d, 1H), 12.1 (br s, 1H). MS m/z 180 (ESI+, MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCCCCBr)NC1CC1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 96.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (525.0 mg, 1.83 mmol) and N-cyclopropyl-10-bromodecanesulfonamide (685.0 mg, 2.01 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-10-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]decanesulfonamide (964.0 mg) as a pale brown oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1.[CH:22](O)=[O:23]>O>[CH:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1)=[O:23]
Reactant: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2N)c1
Reactant: O=CO
Solvent: O
Product: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2NC=O)c1
Yield: 82 %

Procedure:
Added 2-amino-3′,5-di-t-butyl biphenyl (2.0 g, 7.11 mmol) to a solution of formic acid and heated to reflux for 16 hours. After cooling, water (25 mL) was added the product and the precipitate collected by vacuum filtration. The crude product was dissolved into ethyl acetate, washed with water. The organics were dried over magnesium sulfate and concentrated and purified by column chromatography using 10% ethyl acetate and hexanes as the eluants to give the pure N-formyl-2-amino-3′,5-di-t-butyl biphenyl (1.8 g, 82% yield) as determined by GCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:33]([N:35]1[CH2:43][CH:42]2[CH:37]([NH:38][CH2:39][CH2:40][CH2:41]2)[CH2:36]1)[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:38]4[CH2:39][CH2:40][CH2:41][CH:42]5[CH2:43][N:35]([CH2:33][CH3:34])[CH2:36][CH:37]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: CCN1CC2CCCNC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CC2CCCN(CCCOc3cc4c(Nc5ccc(F)c(Cl)c5)ncnc4cc3OC)C2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 34.7 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.80 g), K2CO3 (3.00 g) and 6-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.40 g) in 25 mL of DMF was stirred at 80° C. for 7 h, then cooled to rt, poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.36 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 515.4 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.93 (t, J=4.6 Hz, 3H), 2.21-2.33 (m, 4H), 2.43-2.50 (m, 5H), 2.54-2.60 (m, 2H), 2.98-3.02 (m, 2H), 3.17-3.20 (m, 3H), 3.35-3.41 (m, 1H), 3.48-3.52 (m, 1H), 4.29 (s, 3H), 4.34 (t, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.43 (s, 2H), 7.91 (t, J=4.2 Hz, 1H), 8.47 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([SH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[CH2:22][C:23]([O:25][CH:26]1[CH:30]([O:31][C:32](=[O:34])[CH3:33])[CH2:29][O:28][CH2:27]1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:32]([O:31][CH:30]1[CH2:29][O:28][CH2:27][CH:26]1[O:25][C:23]([CH2:22][S:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])[CH:6]=1)=[O:24])(=[O:34])[CH3:33]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(S)c(Cl)cc1F
Reactant: CC(=O)OC1COCC1OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OC1COCC1OC(=O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 14.0 g of N-(4-chloro-2-fluoro-5-mercaptophenyl)-3,4,5,6-tetrahydrophthalimide, 11.0 g of 4-acetoxytetrahydrofuran-3-yl chloroacetate, 7.46 g of potassium carbonate, 1.5 g of potassium iodide and 150 ml of acetone was refluxed under stirring for 5 hours. After cooling, the salt was filtered off, and the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 14.5 g of a compound described in Table 1 (No. 6) (65%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]/[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:38])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:2][C@H:20]1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:38])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1
Reactant: C[S+](C)(C)=O
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccc(F)cc43)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccc(F)cc34)cc21
Temperature: 55 °C
Reaction time: 7 h
Yield: 45.9 %

Procedure:
Trimethylsulfoxonium iodide (164.4 mg, 0.747 mmol) was added to a suspension of sodium hydride (89.6 mg, 2.24 mmol) (60% dispersion in oil) in DMF (2.0 mL) at room temperature. The mixture was stirred for 15 min after which time a solution of (E)-5-fluoro-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (200 mg, 0.373 mmol) in DMF (1.25 ml) was added. The solution was stirred at 55° C. for 7.0 h prior to quenching reaction mass over 25% NH4Cl solution (10 mL) at room temperature. The product was extracted using ethyl acetate (15 mL×2) and the organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified using silica gel column chromatography (hexane:acetone 80:20 as an eluent) to yield a creamy semi-solid, which was then triturated with hexanes (2.0 mL) to give the title compound as an off-white powder (94 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.46 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 6.78 (m, 1H), 5.72 (s, 2H), 5.68 (d, J=8 Hz, 1H), 3.54-3.48 (m, 3H), 2.34 (br s, 1H), 2.13 (br s, 1H), 0.88 (m, 2H), 0.03 (s, 9H).