Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.CO>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-[4-(trifluoromethyl)benzyl]-1H-indole-7-carboxylate (11.7 g, 35.1 mmol) was dissolved in 350 ml of 1:1 THF/MeOH and 175 ml of 2N KOH (10 eq, 351 mmol). The mixture was stirred at RT for 18 hr. Then the solvents were evaporated under reduced pressure. 2N HCl was added (pH=3) and the aqueous phase was extracted 3× with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and then concentrated under reduced pressure. 1H NMR (500 MHz, DMSO-d6): δ 12.85 (bs, 1H), 7.80 (d, 1H), 7.60 (m, 3H), 7.50 (m, 1H), 7.10 (t, 1H), 7.00 (d, 2H), 6.70 (d, 1H), 5.80 (s, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:10]=[N:11][OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20](=[O:28])[C:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH2:22].Cl[O-].[Na+]>O1CCCC1.O>[CH3:18][O:19][C:20]([C:21]1([CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:12][N:11]=[C:10]([C:9]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:22]1)=[O:28]
Reactant: COc1ccc(C=NO)cc1OC1CCCC1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(C(=O)OC)CC(c2ccc(OC)c(OC3CCCC3)c2)=NO1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound obtained from step b above (1 eq) in tetrahydrofuran, was added dimethylitaconate (2 eq). The reaction mixture was stirred at 60° C. for 0.5 hours followed by the addition of sodium hypochlorite solution. The resulting reaction mixture was stirred at 60-70° C. for 5-6 hours. Tetrahydrofuran was removed under reduced pressure. The residue thus obtained was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution and water. The reaction mixture was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>CS(C)=O>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
To a solution of 7.41 g (0.0576 mole) of 4-chlorophenol dissolved in 150 ml of DMSO was added 2.30 g (0.0576 mole) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0524 mole) of 4-chlorophenyl methyl sulfone was added. The reaction mixture was heated at 160° C. for 3 hrs and cooled. The mixture was poured into a solution of 400 ml of 2 Normal (N) aqueous NaOH and 300 ml of water. The crystalline product was collected by filtration, washed well with water, and dried, which gave 13.8 g (93.2% yield) of product, mp 109°-111° C. Recrystallization from ethanol afforded purified 4-(4-(methylsulfonyl)phenoxy)-1-chlorobenzene, mp 111°-112° C.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:12]=1[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][CH:16]=1)=[O:14].C(O)(=O)C>C(O)C>[NH2:5][C:4]1[N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[C:12]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:11]=3[Cl:10])=[CH:24][CH:23]=2)[N:21]=[N:22][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3c(Cl)cccc3Cl)cc2)c1N
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
A stirred, 65° C. mixture of sodium methoxide (330 mg, 6.11 mmol) in absolute ethanol (20 ml) was treated with 2-cyanoacetamide (527 mg, 6.27 mmol) and kept 10 minutes. The resulting suspension was treated with 4-(2,6-dichlorobenzoyl)benzyl azide (1.6 g, 5.2 mmol), refluxed 2 hours, cooled, treated with glacial acetic acid (600 μl, 629 mg, 10.5 mmol), and evaporated to dryness under vacuum. The residue was chromatographed on a column of silica gel (100 g) eluted with 19:1 (v/v) dichloromethane-methanol to provide 100 mg (5%) 5-amino-1-(4-[2,6-dichlorobenzoyl]benzyl)-1,2,3-triazole-4-carboxamide, m.p. 165°-167° C.
Reaction SMILES: [CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>O>[OH:11][CH2:10][CH2:12][NH:13][CH2:1][C@H:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: NCCO
Solvent: O
Product: OCCNC[C@@H](O)c1ccccc1

Procedure:
5 g of (S)-(+)-styrene oxide and 15.410 mL ethanol amine were stirred at room temperature overnight. The solution is poured into water and the water was extracted with dichloromethane. The combined dichloromethane layers were washed with brine and concentrated in vacuo. The oil was used crude. Assumed quantitative yield carried on to the next step. Theoretical wt: 7.9 g
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=O)=[CH:28][CH:27]=4)[N:20]=3)=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:32][N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:30][CH:31]=4)[N:20]=3)=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the suspension of 96 mg (2.53 mMol; 4 Eq.) of lithium aluminum hydride (Fluka 62420) in 20 mL of THF abs. under Argon at rt is added slowly within 10 min 300 mg (0.633 mMol) of (4-{4-([3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (see Example 31) as a solid; under vigorous foaming. After stirring for 2.5 h at rt, the suspension is cooled to 0° C. and treated dropwise with 20 mL of water. After diluting further with 50 mL of water, the suspension is extracted with ethyl acetate. The combined organic layers are washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica gel, eluting with CH2Cl2/CH3OH (4:1) followed by trituration in diethyl ether to obtain {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=O)=[C:4]([F:19])[CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:19]
Reactant: O=C1C2=C(CCCC2)C(O)N1c1ccc(Cl)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Cl)cc1F
Yield: 87 %

Procedure:
In 30 ml of dichloromethane was suspended 21.0 g of 2-(4-chloro-2-fluorophenyl)-3-hydroxy-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one, and 7.5 ml of thionyl chloride was added to the suspension under stirring over a 20-minute period. The reaction mixture was warmed, stirred at 40° to 45° C. for 1 hour and concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride and, upon addition of hexane, there was produced insoluble matter, which was filtered out. The filtrate was concentrated to dryness under reduced pressure, thereby affording 19.5 g (yield of 87%) of crystals of the subject compound. Recrystallization from cyclohexane yielded white crystals, m.p. 89°-90° C.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:48])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:48])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Yield: 92 %

Procedure:
Following the procedure as described in Example 5, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-phenethylimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 92% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.29-7.14 (m, 5H), 3.92 (t, J=7.2 Hz, 2H), 3.53-3.41 (m, 4H), 2.79 (t, J=7.8 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 332.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:28])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@H:18]([F:28])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile prepared according to example 1 (30 mg, 0.0983 mmol) in DCM (2 mL) at 0° C. was added DAST (0.02 mL, 0.1475 mmol) and the reaction mixture was stirred at same temperature for 2 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with DCM, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative TLC method (40% EtOAc in hexane) provided the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]2[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(O)C>[CH2:32]([N:39]([CH2:18][C@H:17]([OH:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:11]=1)[C@H:40]1[CH2:41][CH2:42][C@H:43]([C:46]2[CH:47]=[CH:48][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:55][CH:56]=2)[CH2:44][CH2:45]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 818 mg (1.82 mmol) of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene and of 450 mg (1.82 mmol) of ethyl trans-4-[4-(benzylamino)cyclohexyl]benzoate in the base form is heated at reflux in 15 ml of absolute ethanol for 16 h. The mixture is cooled, 3 ml of a saturated ethanolic hydrochloric acid solution are added thereto and the mixture is heated at 50° C. for 6 h. The solvent is evaporated and the residue is taken up with a mixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a methylene chloride/methanol/NH4OH (95/5/0.5) mixture. The title compound is obtained in the form of a white solid. [M+H+]=687.
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:23]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[C:19]([N+:20]([O-:22])=[O:21])[C:10]([S:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(SCc2ccccc2)ccc2c1CNCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(SCc3ccccc3)c([N+](=O)[O-])c2C1

Procedure:
A mixture of 17.5 g. (0.052 mole) of 7-benzylthio-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride, 15 ml. of acetic anhydride and 4.5 g. (0.055 mole) of sodium acetate in 150 ml. of acetic acid was heated on a steam bath for one hour, then evaporated. Water and aqueous ammonia was added to the residue until the mixture was basic. The mixture was extracted with methylene chloride, the extracts combined and washed with water, 10% hydrochloric acid, 5% sodium bicarbonate, dried over sodium sulfate and concentrated. Chromatography of the residue on silica (ethyl acetate) gave 2-acetyl-7-benzylthio-8-nitro-1,2,3,4-tetrahydroisoquinoline, melting point 94°-95° C.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]3)[CH2:16][C:15]2=1.C(N(CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH:31][CH2:2][CH2:3][S:4][C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[CH:28]=[N:27]3)[CH2:16][C:15]2=1
Reactant: BrCCSc1cccs1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(NCCSc2cccs2)cn1)CO3
Temperature: 80 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (317 mg, 0.13 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H-pyrazol-4-ylamine (50 mg, 0.13 mmol, 1.0 eq) in acetonitrile (6 mL), followed by triethylamine (19 μL, 0.13 mmol, 1.0 eq). After 72 hours stirring at 80° C., the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel, eluent:cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H pyrazol-4-yl]-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine as a brown viscous oil (9 mg, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cs1
Product: O=C(Cl)c1cc(Cl)cs1

Procedure:
1.63 g (10.0 mmoles) of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem. 13:393 (1976)) was dissolved in 10 ml of thionyl chloride and heated to reflux. After refluxing for 1.5 hours excess thionyl chloride was evaporated, leaving 1.88 g of crude 4-chloro-2-thiophenecarbonyl chloride as a dark brown oil. This acid chloride was dissolved in 10 ml of N,N-dimethylformamide and slowly added to a cooled (ice-water) 40 ml N,N-dimethylformamide solution of 1.75 g (8.33 mmoles) 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine. The reaction was complete in 1 hour. The mixture was poured into 100 ml of 1N hydrochloric acid causing a precipitate to form. The crude solid was filtered, dried and recrystallized to give 1.89 g (5.3 mmoles, 64% yield) of title compound as yellow needles, m.p. 212°-214° C. (2-butanone).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[N:8]([CH2:11][CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[C:9]=[S:10].N(CCS(O)(=O)=O)=C=S.C(N(CC)CC)C>ClCCCl>[O:5]=[C:3]1[CH2:2][S:1][C:9](=[S:10])[N:8]1[CH2:11][CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14]
Reactant: CCOS(=O)(=O)CCN=C=S
Reactant: CCOC(=O)CS
Agent: O=S(=O)(O)CCN=C=S
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)CCN1C(=O)CSC1=S

Procedure:
Ethyl 2-mercaptoacetate (I-A) and ethyl 2-isothiocyanato-ethanesulfonate (I-B) or 2-isothiocyanato-ethanesulfonic acid, alternatively, are dissolved in 1,2-dichloroethane and triethylamine is added. The product ethyl 2-(4-oxo-2-thioxothiazolidin-3-yl)-ethanesulfonate (1-C) can be isolated after e.g. 1 h of stirring and subsequent solvent removement.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38]Br)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>CN(C=O)C.O>[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:7]2[C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][C:2]2([CH3:13])[CH3:1])=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCN2C(=O)c3ccccc3OC2(C)C)cc1)OCC
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazine (0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g, 3.39 mmol) and stirred for 30 min. To this reaction mixture was added a solution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70 g, 2.03 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585) in DMF (1 mL) and stirred for 24 h at 60-70° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent to afford the title compound (0.34 g, 45%) as a liquid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25])=[CH:11]1>CN(C)C=O>[C:1]1([NH:7][C:8]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][CH2:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[CH3:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(CCCN)CCc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)Nc1ccccc1)CCc1c[nH]c2ccccc12

Procedure:
3 ml phenyl isocyanate are added dropwise between 5° and 10° and with stirring to a solution of 5.8 g N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10° and 15° and evaporated. The residue is dried in high vacuum and chromatographed on silicagel using methylene chloride with 6 to 10% methanol, to yield the title compound (M.pt. of the hydrogen maleate 153°-155° with decomposition after crystallization from alcohol/acetone).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].CC1C=CN=C(N)C=1C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:22][N:21]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1F
Agent: Cc1ccnc(N)c1C
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1F

Procedure:
Prepared according to Method D, Step A from (3-chloro-2-fluorophenyl)(3-fluoro-4-methoxyphenyl)methanone (0.80 g, 2.83 mmol), hydrazine hydrate (1 mL), dimethyl-aminopyridine (0.390 g) and pyridine (5 mL). The reaction mixture was combined with a previous batch at this stage and the title compound was obtained as a white solid and recrystallized from ethyl acetate/hexane (1.30 g, 4.79 mmol, 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ncn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-N-(2-methoxy-1-methylethyl) [4,4′-bipyrimidine]-6-amine (i.e., the product of Step C) (100 mg, 0.357 mmol) and 3-chloroaniline (57 mg, 0.45 mmol) in 1,4-dioxane (3.5 mL) under a nitrogen atmosphere was added p-toluenesulfonic acid monohydrate (57 mg, 0.30 mmol). The resulting mixture was stirred at 100° C. for 18 h. The solution was concentrated under reduced pressure to give a yellow solid residue. The residue was then purified on silica gel eluted with 40% ethyl acetate in hexanes, followed by acetone to give 113 mg of title compound as a solid.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:45]=[N:46][CH:47]=[N:48][CH:49]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:10][CH2:11]1)=[O:17]
Reactant: Brc1cncnc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cncnc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (275 mg, 0.44 mmol) is coupled to 5-bromopyrimidine (79 mg, 0.48 mmol) using Method B to give the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].Cl.O>CC(C)=O>[OH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH:9]=2)[CH:3]=[O:2])[CH2:15][CH2:14]1
Reactant: COC(OC)c1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Yield: 96.4 %

Procedure:
To a solution of 4.3 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde dimethylacetal in 40 ml of acetone was added 40 ml of 2N hydrochloric acid. After refluxing for 15 min, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under a reduced pressure to give 3.5 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde.