Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]#[N:40])[C:10]2=[O:44])=[CH:5][CH:4]=1.[OH-:45].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]([NH2:40])=[O:45])[C:10]2=[O:44])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: N#Cc1ccccc1
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1

Procedure:
(±)-3-(3-(4-Methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzonitrile (0.25 g; 0.41 mmol) (from Example 7 supra) was dissolved in dimethyl sulfoxide (2.5 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 750 μL; 0.75 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 130 μL; 1.27 mmol) was then added. The cooling bath was removed. The solid went back into solution and a new solid precipitated out. After 3 hours the reaction mixture was diluted with water. The solid was collected, washed with water and air-dried under the house vacuum. Purification by flash chromatography (Biotage 12S; 90:10 to 60:40 chloroform-methanol gradient) and then crystallization from methanol-ethyl acetate gave (±)-3-(3-(4-methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzamide as a white solid. (Yield 35.7 mg; 14.3%). A second crop was collected by addition of ether to the mother liquor. (Yield 87.8 mg; 35.1%). Melting Point: 243–251° C. HR-MS(ES+) m/z Calculated for C34H38N8O3 ([M+H]+): 607.3140; Found: 607.3144.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=1)[C:8](N(OC)C)=[O:9])(=[O:3])[CH3:2].[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[Li+].COCCCC.C[Mg]Br.Cl>C1COCC1.C(OCC)(=O)C.O>[C:8]([C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:16]=[C:15]([S:17]([F:22])([F:18])([F:20])([F:21])[F:19])[CH:14]=1)(=[O:9])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: CCCCOC
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Yield: 82.3 %

Procedure:
3-Acetylamino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (1.2 g) was dissolved in absolute THF (30 ml) and stirred at 0° C. with lithium hexamethyldisilazide (721 μl; density: 0.8 g/1; 23% in tent-butyl methyl ether) for 30 min. At 0° C., methylmagnesium bromide (2.87 ml, 3 M in diethyl ether) was then added dropwise while stirring. After stirring at RT for 2.5 h, further methylmagnesium bromide (1 ml, 3 M in diethyl ether) was added and the mixture was stirred again for 2.5 h. For workup, 1 N hydrochloric acid was added dropwise while cooling with ice, followed by water and ethyl acetate. The organic phase was removed and the water phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered and concentrated. The crude product (1.03 g) was combined with a crude product prepared in the same way (75 mg) and purified using silica gel with dichloromethane-methanol as the eluent. 860 mg of the desired compound were obtained. LC-MS rt: 1.34 min [M+H]+: 304.0
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: CCSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 3,4 gm (0.01 mol) of 8-ethylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p. 197°-199° C.) in 100 ml of dimethylsulfoxide was slowly poured, while stirring, into a solution of 4.3 gm (0.05 mol) of piperazine in 75 ml of dimethylsulfoxide at 40° C., and the mixture was stirred for 1 hour at 40° C. The reaction mixture was then taken up in about 1 liter of water, whereby the reaction product slowly precipitated in crystalline form. After standing for a short period of time, the precipitate was suction-filtered off, washed with water and dried at about 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH2:11].Cl[C:13](OCC)=O.[NH4+].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH:11][CH3:13]
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichlorophenyl)ethylamine (1 ml, 0.00663 mol) and TEA (1.4 ml, 1.5 eq) were dissolved in THF (20 ml) and cooled in an ice-water bath. Ethyl chloroformate (0.95 ml, 1.5 eq) was added slowly and the mixture stirred at rt for 2 h. NH4Cl (sat) was added and the mixture extracted with EtOAc, the combined extracts were washed with NH4Cl (sat), and dried (MgSO4). The organic solvent was removed and the residue dissolved in Et2O (5 ml). This solution was slowly added to a slurry of LiAlH4 (530 mg, 2 eq) in Et2O (15 ml) at −78° C. The mixture was allowed to slowly warm to rt and stirred overnight. The mixture was cooled in an ice-water bath and water (0.53 ml), 15% NaOH (0.53 ml), and water (1.5 ml) added sequentially. The mixture was stirred vigorously for 30 min and the resulting slurry filtered. The filtrate was concentrated under reduced pressure to give 1.2 g of [2-(2,6-dichlorophenyl)ethyl]methylamine.
Reaction SMILES: C1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[C:10]([CH:20]=[O:21])=[CH:9][CH:8]=2)CCCC1>Br.C(O)(=O)C>[OH:6][C:7]1[C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]([CH:20]=[O:21])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OC2CCCC2)c2oc3ccccc3c12
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c2oc3ccccc3c12
Temperature: 0 °C

Procedure:
Intermediate 18 was heated in HBr (30-33%) in glacial acetic acid (25 ml) at 50° C. for 7-8 h The reaction contents were poured in ice-water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, and extracted with 10% sodium hydroxide (3×25 ml) solution. The aqueous layer was acidified with conc. HCl to give a white precipitate which was filtered and air dried to obtain the crude product as a white solid (3.2 gm).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[F:15][C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[F:15][C:16]1[CH:17]=[C:18]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(F)(F)F
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.71 g, 4.5 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Fluoro-4-(phenylsulfonyl)benzeneamine (0.75 g, 3.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered through Celite. The Celite was washed with methylene chloride (75 mL), the organic extract dried (MgSO4) and concentrated in vacuo to a tan solid. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (0.79 g, 68%); mp 147°-149° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 7.65-7.69 (m, 4H, aromatic+OH) 7.74 (d, 1H, J=7.2 Hz, aromatic) 7.83-7.94 (m, 3H, aromatic) 8.02 (t, 1H, J=8.3 Hz, aromatic) 10.61 (s, 1H, NH). MS (CI, CH4): 392 (M+1).
Reaction SMILES: CN1CCOCC1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=O.[S:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH2:30])[CH:24]=[C:25]3[C:29]=2[NH:28][N:27]=[CH:26]3)=[CH:19][C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]1=2.CN(C=O)C>CC#N.C(Cl)Cl.CC#N>[S:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH:30][C:13]([C:9]3[O:8][CH:12]=[CH:11][CH:10]=3)=[O:15])[CH:24]=[C:25]3[C:29]=2[NH:28][N:27]=[CH:26]3)=[CH:19][C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]1=2
Reactant: O=C(O)c1ccco1
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
In a 20 mL vial, a solution of N-methylmorpholine (0.060 g, 0.60 mmol) in MeCN/CH2Cl2 (1:1, 0.688 mL) was added to Si-dichlorotriazine (SiliCycle, Inc; 0.60 mmol/g, 0.74 g, 0.44 mmol). Then, a solution of 2-furoic acid (0.021 g, 0.19 mmol) in MeCN (0.925 mL) was added and mixed for about 1 min., prior to the addition of a solution of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 0.039 g, 0.15 mmol) in MeCN/CH2Cl2 (1:1, 0.688 mL). The reaction mixture was shaken at ambient temperature for about 16 hours. The crude reaction solution was mixed with DMF (5 mL) to aid in solubility, eluted through a Si-carbonate (SiliCycle, Inc; 1 g, 6 mL) cartridge using MeOH (approx 3 mL), and concentrated in vacuo. The crude product was then purified by preparative HPLC (Waters Symmetry C8 column (25×100 mm, 7 μm particle size) using a gradient of 10%-100% CH3CN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min) to afford furan-2-carboxylic acid (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amide (0.0025 g, 4.7%); RP-HPLC (Table 1, Method 1) Rt 2.51 min; m/z: (M+H)+ 360.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][OH:15].Cl.N1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:15][CH2:14][CH2:13][Br:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: O=C(C=Cc1ccccc1)OCCBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
35.3 g (0.212 mol) of cinnamic acid chloride and 100 mL of methyl ethyl ketone were placed in a reaction vessel and stirred at room temperature under a nitrogen atmosphere. Then 28.2 g (0.225 mol) of 2-bromoethanol and 21 g of pylidine were dissolved in 100 mL of methyl ethyl ketone. The resulting solution was added dropwise in the aforementioned reaction vessel at room temperature, and then refluxed with stirring for 2 hours. After cooling the solution, pyridine hydrochloride was precipitated and then separated from the solution by filtration. The filtrate was concentrated and then dissolved in methylene chloride. The solution of methylene chloride was poured into a separating funnel and washed with water. Then the solution was dried with sodium sulfuric anhydride and concentrated. Thus 47 g (86.9% yield) of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[C:19]([F:18])=[CH:24][CH:23]=[CH:22][C:21]=2[F:25])[CH2:7]1
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1c(F)cccc1F)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 66.4 %

Procedure:
Example 52 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and 2,6-difluorophenylacetic acid (0.035 g) to give thetitle compound (0.057 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][C:12](=O)[CH3:13])[CH:5]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:21]3[C:20](=[CH:19][C:18]([Br:17])=[CH:23][CH:22]=3)[NH:24][C:12]=2[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(SCC(C)=O)c1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1

Procedure:
3-(2-Oxo-propylsulfanyl)-benzoic acid methyl ester (3.65 g, 16.29 mmol) and 3-bromophenylhydrazine hydrochloride (4.01 g, 17.92 mmol) were mixed together in t-BuOH (100 mL) and heated to reflux for 1 hour. After cooling the reaction was concentrated then submitted to standard workup procedure and the crude mixture was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford a separable 5:4 mixture of regioisomers wherein the title compound was the major product.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]=4)[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:40].[Na+].OO>C1COCC1.C(OCC)C.O>[C:1]([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:12]([CH2:13][CH2:14][C:15]3[C@H:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]4[OH:40])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(OC(=O)c2ccccc2)C(C)(C)C1CC3
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC(O)[C@H]2C3=C(CC[C@@]21C)[C@@]1(C)CCC(OC(=O)c2ccccc2)C(C)(C)C1CC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.04 g of 3-benzoyloxy-4,4-dimethylcholesta-8,14-diene (Step A) was dissolved in 50 ml of THF, and 360 ml of 1M borane in THF was added dropwise at 0° C. The mixture was stirred at ambient temperature overnight, cooled to 0° C., and 140 ml of water was added dropwise, followed by 360 ml of 10% sodium hydroxide and 378 ml of 30% hydrogen peroxide. After stirring for 90 mutes, 100 ml of diethyl ether was added to the mixture and the aqueous phase extracted twice with diethyl ether. The combined organic phases were washed twice with sodium bisulphite solution and then with water. After evaporation, the product was purified by chromatography on SiO2 (2% diethyl ether in toluene) to yield 0.62 g of 3-benzoyloxy-4,4-dimethylcholest-8-en-15-ol.
Reaction SMILES: [CH2:1]1[N:9]2[C:5](=[N:6][C:7]([NH:10]C(C(F)(F)F)=O)=[CH:8]2)O[CH:3]=[C:2]1[Br:17].[CH2:18]1COCC1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Br:17][C:2]1[CH:3]=[CH:18][C:5]2[N:9]([CH:8]=[C:7]([NH2:10])[N:6]=2)[CH:1]=1
Reactant: O=C(Nc1cn2c(n1)OC=C(Br)C2)C(F)(F)F
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cn2cc(Br)ccc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a 250 mL round-bottomed flask was added N-(6-bromoH-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (3.50 g, 11 mmol), THF (15 mL), methanol (15 mL), water (15 mL) and potassium carbonate (16 g, 114 mmol). The mixture was stirred at 60° C. for 16 h. After cooling to rt, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (4×75 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH/CH2Cl2) afforded the title compound (1.01 g, 42%). MS (ESI, positive ion) m/z: 212 (M(79Br)+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10](C)[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH3:22][CH2:23][CH2:24][O:25][C:26](Cl)=[O:27]>>[CH2:24]([O:25][C:26](=[O:27])[NH:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:4]=1)[CH2:23][CH3:22]
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)NCc1cncc(-c2[nH]c3cc(Cl)ccc3c2C#N)c1

Procedure:
2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and N-propyl chloroformate are processed according to the method described in Example 190 to give [5-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acid propyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.3 Hz, 3H), 1.58-1.74 (m, 2H), 3.83 (s, 3H), 4.06 (t, J=6.6 Hz, 2H), 4.49 (s, 2H), 7.38 (dd, J=8.6, 1.77 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 383.1260 [(M+H)+ Calcd for C20H20ClN4O2: 383.1275].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13].O.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:16]([NH:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)Cc1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CNC(=O)c1ccccc1)Cc1cc(Br)ccc1Cl
Reaction time: 3 h

Procedure:
A mixed solution of the above 1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.70 g) in ethyl acetate (30 ml)-water (15 ml) was cooled to 0° C. Added thereto were benzoyl chloride (0.99 ml) and sodium hydrogen carbonate (2.39 g), and the mixture was stirred at the same temperature for 3 hours. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=95:5) to give 1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) as a colorless solid. APCI-Mass m/Z 366/368 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Reactant: c1cn[nH]c1
Product: c1cnn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:18][O:19][CH2:20]Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:10][CH2:18][O:19][CH3:20])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1c(Br)cccc1C=O
Reaction time: 0.75 h

Procedure:
To 3-bromo-2-hydroxybenzaldehyde (1.33 g, 6.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.81 g, 8 mmol) then chloromethyl methyl ether (0.56 g, 7 mmol). The mixture was stirred for 45 minutes and partitioned between CH2Cl2 and saturated NaHCO3(aq). The crude material was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to afford the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20](=[O:25])[C:19]=3[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC2=C1CCC(=O)N2C1CCN(Cc2ccccc2)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CCc2c(O)cccc2N1C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 21.4 %

Procedure:
1-(1-Benzyl-4-piperidinyl)-5-oxo-3,4,5,6,7,8-hexahydrocarbostyril (10.0 g) is dissolved in chloroform (500 ml) and thereto is added N-bromosuccinimide (5.78 g). The mixture is refluxed with stirring for 2 hours. Thereto are added N-bromosuccinimide (5.00 g) and triethylamine (50 ml) and the mixture is refluxed with stirring for 3 hours. After cooling, the reaction mixture is washed twice with 30% aqueous sodium thiosulfate solution (200 ml) and once with saline solution (500 ml) and then dried with magnesium sulfate. The solvent is evaporated off and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=40:1) and recrystallized from ethanol/water to give 1-(1-benzyl-4-piperidinyl)-5-hydroxy-3,4-dihydrocarbostyril (2.13 g) as colorless needles, m.p.: 183°-184° C.
Reaction SMILES: [O:1]=[S:2](Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:15])[CH2:13][OH:14])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>CC#N>[C:19]([O:18][C:17]([N:16]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=2)([CH3:15])[CH2:13][O:14][S:2]1=[O:1])=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of SOCl2 (5.7 mL, 2.5 eq) in dry CH3CN (37 mL) under argon was cooled to −40° C. was added tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R4=Me) (10.3 g, 31 mmol) in dry CH3CN (27 mL) was added dropwise, followed by the addition of dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowed to warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc (30 mL) was added and the precipitate was filtered off. The filtrate was concentrated in vacuo to give 10.4 g (89%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide as a colorless oil. 1H NMR (CDCl3) 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53 (m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s, 9H).