Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH:9]=[N:8][NH:7][C:6]1=[O:10].[OH-].[Na+].[Br:17]Br>O>[Br:17][C:9]1[N:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[F:1])[C:6](=[O:10])[NH:7][N:8]=1
Reactant: BrBr
Reactant: O=c1[nH]ncn1Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc(Br)n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
The product from Step b (3.35 g, 17.3 mmol) is placed in 37 ml water together with sodium hydroxide (970 mg, 24.2 mmol). Bromine (893 μl, 17.3 mmol) is added dropwise with stirring at RT. During the addition, a light brown solid precipitates. Stirring is continued overnight at RT. The precipitated solid is filtered off at the pump, washed with a little water and then dried under high vacuum. 4.25 g of the target product of adequate purity (ca. 83% by LC/MS) are obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37][NH2:38]>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2ccc(Cl)cc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:8]1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]2[CH2:42][CH2:41][CH2:40][C:39]([C:43](Cl)=[O:44])=[CH:38][C:37]=2[CH:46]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]2[CH2:42][CH2:41][CH2:40][C:39]([C:43]([N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:8][CH:9]3[CH2:13][CH2:14][CH2:15][OH:16])=[O:44])=[CH:38][C:37]=2[CH:46]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COc1cc(CN2CCNC(CCCO)C2)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CCCO)=C2
Yield: 70.8 %

Procedure:
To a mixture of 4-(3,4,5-trimethoxybenzyl)-2-piperazine propanol (1.0 g) obtained in Reference Example 32, triethylamine (1.5 g) and methylene chloride (20 ml) is added dropwise at 0 ° C, while stirring, a solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (713 mg) in methylene chloride (5 ml). The mixture is stirred for 2 hours and there is added an aqueous solution of sodium hydrogencarbonate, followed by shaking. The organic layer is separated, washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-hexane methanol=5:4:1), followed by recrystallization from ethyl acetate to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)-2-piperazine propanol as colorless prisms (1.05 g), m.p. 144-145° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)ccc1Cl
Yield: 32.3 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,5-dichlorophenylboronic acid (available from Combi-Blocks Inc.; 76 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,5′-dichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (32 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.54-7.57 (m, 1H), 7.49 (s, 1H), 7.47 (s, 2H).
Reaction SMILES: [S]Cl.[CH2:3]([NH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[OH-].[Na+].[S:14](Cl)(Cl)(=O)=O.[CH3:19][NH:20][C:21](=[O:34])[O:22][C:23]1[C:31]2[O:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CCCCCC.O>[CH2:3]([N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[S:14][CH2:19][NH:20][C:21](=[O:34])[O:22][C:23]1[C:31]2[O:30][C:29]([CH3:32])([CH3:33])[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCCCNCCCC
Agent: [Na+]
Agent: [OH-]
Agent: [S]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: CCCCN(CCCC)SCNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 10 °C
Yield: 93 %

Procedure:
Over a period of 24 minutes a solution of sulfur monochloride (170.8 g., 1.27 mole) in 385 ml of hexane was added to a stirred mixture of dibutylamine (284.4 g, 2.2 mole) 263 ml of hexane, sodium hydroxide (106.3 g, 2.66 mole), and 801 ml of water. Addition rate was controlled to prevent the temperature from rising above 40° C. The mixture was stirred for an additional twenty minutes, and the aqueous layer was removed. The thermometer, stirrer blades, and reactor walls above the mixture were wiped to remove any moisture. Sulfuryl chloride (148.5 g, 1.1 moles) was added dropwise to the stirred mixture under nitrogen over a period of 19 minutes at a temperature of 20° C. 2,3-Dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (98%, 451.4 g, 2.0 moles) was added to the mixture, followed by dropwise addition of triethylamine (354.2 g, 3.5 mole) over a period of 28 minutes. The mixture was stirred for two hours from the start of addition at 35° C. At the end of this time the mixture was cooled to 10° C. and 880 ml of water was added at a rate slow enough to keep the temperature at or below 20° C. The mixture was stirred for five minutes, then vacuum-filtered. The layers were separated and the organic layer was concentrated to provide 763.6 g of 93% (by hplc) 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dibutylaminothio)methylcarbamate (93% chemical yield based on the starting carbamate). During the filtration 15.88 g of unreacted 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate and tars was recovered.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:1]1[C:6]2[CH2:7][N:8]([C:29]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:33][CH:32]=3)=[O:30])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.1 %

Procedure:
To a mixture of 0.197 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 0.402 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride in 5 ml of dichloromethane (cooled in ice bath) is added dropwise 0.154 g of N,N-diisopropylethylamine in 2 ml of dichloromethane. The mixture is stirred at room temperature under argon for 2 hours. The mixture is poured into water and the organic layer separated. The organic extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness to give 0.65 g of solid. The solid is purified by thick layer chromatography on silica gel with hexane-ethyl acetate (2:1) as solvent to give 0.110 g of a glass, m.p. 107° C.-122° C. Anal. Found: C, 80.8; H, 4.9; N,6.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-:32].[K+].[K+].O>CN(C)C=O>[OH:32][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCO
Temperature: 60 °C
Reaction time: 120 h
Yield: 5.7 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (363 mg) and water (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 5 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 6%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[CH2:11][CH:10]2[CH:12]([NH:13][CH3:14])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1)=[O:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([N:13]([CH3:14])[CH:12]1[CH:10]2[CH2:9][CH2:8][CH:7]1[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:16])([F:1])[F:15])[CH2:11]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNC1C2CCC1CN(C(=O)C(F)(F)F)C2
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: CN(Cc1ccccc1)C1C2CCC1CN(C(=O)C(F)(F)F)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]-1-ethanone (see step (v) above; 4.5 g, 16 mmol), benzylchloride (3.0 g, 16 mmol) and TEA (6.6 mL) in MeCN (50 mL) was stirred at 60° C. overnight. The mixture was evaporated and then DCM and water were added. The organic phase was washed with NaHCO3 solution, dried (Na2SO4) and then evaporated. The resulting crude product was purified by chromatography on silica gel (DCM eluant) to give 2.2 g (42%) of the sub-title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)[CH:7]=1)CCC.[I:29]I>C1COCC1>[I:29][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)[CH:7]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccc3cnccc3c2)no1
Solvent: C1CCOC1
Product: Ic1cc(-c2ccc3cnccc3c2)no1
Temperature: 80 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
To a solution of 6-(5-(tributylstannyl)isoxazol-3-yl)isoquinoline (1.00 g, 2.1 mmol) in 20 mL of THF in a sealable tube was added iodine (0.52 g, 2.1 mmol). The tube was sealed and heated to 80° C. by immersion in an oil bath. After 12 hours, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 2.5% MeOH/DCM), affording 6-(5-iodoisoxazol-3-yl)isoquinoline (0.60 g, 90% yield) as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.52 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.12 (dd, J=1.6 Hz, 8.6 Hz, 1H), 7.92 (d, J=5.7 Hz, 1H).
Reaction SMILES: C([Li:5])CCC.Br[C:7]1[CH:27]=[CH:26][C:10]2[O:11][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.[S:28](=[O:30])=[O:29]>CCCCCC.C(OCC)C>[Li+:5].[C:14]1([C:12]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:26]=[CH:27][C:7]([S:28]([O-:30])=[O:29])=[CH:8][C:9]=3[O:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S=O
Reactant: [Li]CCCC
Reactant: Brc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S([O-])c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Product: [Li+]
Temperature: -55 °C
Reaction time: 1 h

Procedure:
A solution of butyllithium (0.6M) (74 ml) in n-hexane are mixed with 116 ml of diethyl ether and cooled to -55° C. Thereupon, a solution of 40.0 g of 5-bromo-2,2-diphenyl-1,3-benzodioxol in 170 ml of diethyl ether is added dropwise. The reaction mixture is stirred for 1 hour, whereby the temperature rises to -15° C. Subsequently, the mixture is cooled to -50° C. and dry sulphur dioxide gas is introduced for 45 minutes. The excess sulphur dioxide gas is removed by passing dry argon through the mixture for 1 hour. The reaction mixture is left to come to room temperature. There thereby results a white precipitate, which is filtered off and dried. There are obtained 22.2 g of 2,2-diphenyl-1,3-benzodioxol-5-sulphinic acid lithium salt as white crystals of m.p.>300° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[C:15]3[C:6](=[CH:7][C:8]4[C:9]5[C:14]=3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=5[CH:23]=[CH:24][CH:25]=4)[CH:5]=[CH:4][CH:3]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Cc5ccc(Cl)cc5)c4c(c23)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 7 mL of dichloromethane was magnetically stirred at 20° C. 113 μL (2 molar equivalents) of 4-chlorophenylacetyl chloride were added. The mixture was magnetically stirred at room temperature during 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 122 mg (yield: 84%). of the desired product (formula above) as an orange powder which was characterized as follows:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)#[N:2].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)C>[Si:20]([O:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cc(CO)ccn1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of 2-cyano-4-hydroxymethylpyridine (step 1, 3.63 g, 27.06 mmol) in DMF (50 ml) were added imidazole (4.42 g, 64.95 mmol) and TBDMSCl (4.89 g, 32.47 mmol) at room temperature. After stirring for 1 h, the mixture was diluted with diethyl ether (300 ml), washed with water (100 ml×4), and dried (MgSO4). Removal of solvent gave the title compound. 1H-NMR (CDCl3) δ: 8.65 (1 H, d, J=5.1 Hz), 7.68 (1 H, s), 7.46 (1 H, d, J=4.9 Hz), 4.78 (2 H, s), 0.96 (9 H, s), 0.13 (6 H, s).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: OCCOCCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCOCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a solution of diethylene glycol (1.118 g, 10.54 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.150 g, 39%). Mass (m/z): 386.2 (M++1), 384.1 (M+−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][N:15]=[CH:14]2.S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[CH:14][N:15]([CH3:22])[N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccc(-c2cccc3cn[nH]c23)c(Cl)c1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1cc2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 2.5 °C

Procedure:
A solution of 7-(2,4-dichloro-phenyl)-1H-indazole (4; 1.12 g, 4.27 mmol) and dimethyl sulfate (0.405 mL, 4.28 mmol) in 15 mL of toluene was stirred at 110° C. for 17 h, allowed to cool, then chilled at 0-5° C. The mixture was carefully washed with 15 mL of a saturated aqueous NaHCO3 solution, dried over MgSO4, filtered (rinsing with diethyl ether), and concentrated to an orange oil Column chromatography (0→33% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole as a viscous yellow oil (5; 0.92 g, 78%).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.[N:16]1[N:17]=[N:18][N:19]2[CH:24]=[C:23]([C@@H:25]3[CH2:27][O:26]3)[CH:22]=[CH:21][C:20]=12>CO>[CH3:1][C@@H:2]([NH:15][CH2:27][C@@H:25]([C:23]1[CH:22]=[CH:21][C:20]2[N:19]([N:18]=[N:17][N:16]=2)[CH:24]=1)[OH:26])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: COc1ccc2[nH]cc(C[C@@H](C)N)c2c1
Solvent: CO
Product: COc1ccc2[nH]cc(C[C@@H](C)NC[C@H](O)c3ccc4nnnn4c3)c2c1

Procedure:
A solution of 553 mg of partially resolved (R)-1-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (R. A. Glennor et al, Biol Psychiatry, 18,493 (1983) and 452 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane in 10 ml of methanol under nitrogen was heated at reflux for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue (1.0 g) purified by careful preparative TLC on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 515 mg of (R)-α-[[(1(R)-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol plus 11.6 mg of the adduct resulting from the small amount of (S)-amine present in the starting material.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 33 %

Procedure:
The product from Example 93, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 93, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1H) 7.93 (d, J=2.94 Hz, 1H) 7.87 (d, J=7.72 Hz, 1H) 7.53-7.75 (m, 6H) 7.49 (t, J=6.25 Hz, 1H) 7.39 (d, J=2.57 Hz, 1H) 6.57 (s, 1H) 5.68 (dd, J=7.91, 2.02 Hz, 1H) 4.19 (d, J=5.15 Hz, 2H) 3.47 (s, 2H) 3.21 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [H-].[Na+].[S:3]1C=CC=C1CC(O)=O.Br[CH:13]([C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=[O:26])[CH2:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16].[CH2:37]([OH:39])[CH3:38]>>[C:37]([S:3][CH:13]([C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=[O:26])[CH2:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:39])[CH3:38]
Reactant: O=C(c1ccc2ccccc2c1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)Cc1cccs1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To 30 ml. of ethanol cooled in an ice bath is added 380 mg. of sodium hydride (60% dispersion in oil), and 0.67 ml. of thiolacetic acid. After stirring for 30 minutes, 2.55 g. of 1-[3-bromo-3-(2-naphthoyl)propionyl]-L-proline is added and the mixture is stirred for 18 hours. The solvent is removed under vacuum. The residue is chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (7.5:2.5:0.2) as solvent to give 1.2 g. of the product of the example, as a white glass, [α]D -36(c, 0.96 ethanol).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1)[CH3:18].Cl.CCCCCCC>ClCCl>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:28])=[CH:22][CH:21]=1)[CH3:18]
Reactant: CN1CCC(NCc2ccc(F)cc2)CC1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCN(C)CC2)cc1
Reaction time: 20 h

Procedure:
50ELH4 (0.11 g, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added and the vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeated and the product dissolved in dichloromethane (1 ml) and HCl (1 eq., 2 M in ether) is added. This mixture was added drop-wise to an excess of heptane whereupon the salt precipitated. Yield 31.1 mg (16%), UV/MS: 94/100 (M+ 385), tr (A, MS) 2.573.