Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][C:14]([CH3:17])=[N:15][CH:16]=[C:11]2[C:10]([C:18]#[N:19])=[N:9]1.[Cl-].[NH4+:26].C(O)(=O)C>CO>[F:4][C:5]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][C:14]([CH3:17])=[N:15][CH:16]=[C:11]2[C:10]([C:18](=[NH:26])[NH2:19])=[N:9]1
Reactant: [NH4+]
Reactant: Cc1ncc2c(C#N)nn(Cc3cccc(F)c3F)c2n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 0.73 ml (3.35 mmol) of a 25% sodium methoxide solution was initially charged in methanol, and 1.040 g (purity 92%, 3.35 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile dissolved in 4 ml of absolute methanol were added. The mixture was stirred at RT for 1 h. Subsequently, 215 mg (4.03 mmol) of ammonium chloride and 786 mg (13.08 mmol) of acetic acid were added and the mixture was heated to reflux for 2 h. The reaction mixture was concentrated, and the residue was admixed with 10 ml of ethyl acetate and 15 ml of water and basified (pH=10) with 2N sodium hydroxide solution. The mixture was stirred at RT for 1 h, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate, concentrated and dried under high vacuum. 840 mg (purity 85%, 70% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(OC)(O[CH3:43])(=O)=O>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:43])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(-c2ccc3ccc(C45CC6CC(CC(C6)C4)C5)cc3c2OCCCCCCO)cc1
Product: COCCCCCCOc1c(-c2ccc(C(=O)OC)cc2)ccc2ccc(C34CC5CC(CC(C5)C3)C4)cc12
Yield: 11.2 %

Procedure:
Following the procedure of Example 12(a), but reacting 870 mg (1.7 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxyhexyloxy-2-naphthyl]benzoate with 160 μl (1.7 mmol) of dimethyl sulphate, 100 mg (14%) of the expected compound were obtained, which compound had a melting point of 141°-3° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1(C(OC(C)(C)C)=O)[CH2:33][CH2:32][CH2:31][C@@H:9]1[C:10]([NH:12][C@@H:13]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]>ClCCl>[NH:8]1[CH2:33][CH2:32][CH2:31][C@@H:9]1[C:10]([NH:12][C@@H:13]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Distilled TFA (4.60 ml, 59.6 mmol) was added dropwise to a solution of N-Boc-D-Pro-D-Phe-OBn (2.70 g, 5.96 mmol) in dry dichloromethane (5.0 ml), and the mixture was stirred at room temperature for 4 hours. TFA and solvent were then removed by evaporation under reduced pressure, and the resulting residue redissolved in chloroform. Water and solid potassium carbonate were added in amounts sufficient to achieve & pH of 10 in the resulting aqueous solution, and the aqueous layer was then extensively extracted with chloroform. The combined organic layers were dried over MgSO4 and concentrated to yield crude D-Pro-D-Phe-OBn as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11](C(O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[NH:3]1.C([O-])(=[O:19])C.[K+].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O[Li].O>C(O)(=O)C.C1C=CC=CC=1.O>[OH:19][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[NH:3][C:2]1([CH3:16])[CH3:1]
Reactant: CC(=O)[O-]
Reactant: CC1(C)NC(=O)c2ccccc2C1C(=O)O
Agent: [K+]
Agent: [Li]O
Agent: [Pb+4]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)NC(=O)c2ccccc2C1O
Temperature: 25 °C

Procedure:
To a solution of 3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (5.0 g, 22.8 mmol) in acetic acid (450 mL) and benzene (160 mL) is added successively, potassium acetate (15.7 g, 160 mmol), cupric acetate (210 mg, 1.14 mmol), and lead (IV) acetate (18.2 g, 41.1 mmol). The green solution is heated to reflux for 4 h, at which time additional lead (IV) acetate (2.0 g 4.5 mmol) is added. After a total of 5 h at reflux the reaction is cooled to room temperature and quenched by the addition of ethylene glycol (ca. 5 mL). The reaction is concentrated in vacuo to near dryness. The resulting dark green oil is dissolved in ethyl acetate and stirred vigorously while cautiously treating with saturated aqueous sodium bicarbonate followed by solid NaHCO3 until the aqueous layer reached a pH greater than 8. The layers are separated and the aqueous layer is extracted 3 times with ethyl acetate. The organic layer is dried with Na2SO4 filtered and concentrated. The resulting brown oil is then dissolved in THF (200 mL). Water (40 ml) and LiOH.H2O (5.0 g, 118.6 mmol) are added. The reaction mixture is heated to 45° C. and stirred for 18 h, at which time it is cooled to room temperature. The reaction is concentrated in vacuo to ca. ¾ of its original volume, diluted with methylene chloride and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted 3 times with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford a brown oil, which is pre-adsorbed on silica gel for further purification. Purification by silica gel flash chromatography (dichloromethane-methanol, 99:1 to 23:2) furnished 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one as an off-white foam; MS (ESI) m/z 192.1 (M+H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][O:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O>CO>[C:10]1([C:8](=[N:4][CH2:3][CH2:1][OH:2])[CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:6][CH3:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Product: COC(C(=NCCO)c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethanolamine, 8.34 g (0.137 mole) and 4.52 g (0.020 mole) of 2-methoxy-1,2-diphenylethanone were mixed together and heated at 120° C. under a gentle stream of nitrogen for 2 hr. Mass spec analysis indicated none of the 2-methoxy-1,2-diphenylethanone remained. The mixture stood at ambient temperature for 16 hr, after which it was dissolved in 20 ml of methanol. The solution was poured into 100 ml of water. A yellow oil separated which became semisolid after 1 hr. The semisolid was extracted twice with 50 ml portions of methylene chloride. The extract was dried over magnesium sulfate, filtered, and concentrated to give 5.04 g of yellow oil (94%) which began to solidify on standing. Trituration with petroleum ether gave 2.19 g of off-white solid after filtration. The filtrate was concentrated to give an additional 2.25 g of yellow oil which was identical to the white solid and which crystallized on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH2:23])[C:7]=2[CH:24]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-:37])=[O:36])C=1.C(N(CC)CC)C.O[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:35](=[O:36])[O:37][CH2:46][CH2:47][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[C:7]=2[CH:24]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc2c(c1)[C@@H](N)CCc1cc(OC)c(OC)c(OC)c1-2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@H](NC(=O)OCCN1CCOCC1)CCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 60 °C
Yield: 64 %

Procedure:
A solution of (5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine [Collect. Czech. Chem. Commun. 1999, 64(2), 217-228] (0.263 g; 0.8 mmol), 4-nitrophenylchloroformate (0.177 g; 0.88 mmol) and triethylamine (0.123 ml; 0.88 mmol) in acetonitrile (5 ml) was stirred under argon atmosphere for 2 hours at ambient temperature; 4-(2-hydroxyethyl)morpholine (0.145 ml; 1.2 mmol) in solution in acetonitrile (2 ml) was then added to the above solution. The mixture was heated at 60° C. overnight. After evaporation to dryness, the residue was purified by flash chromatography, eluted with ethanol/dichloromethane (4/96) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:42]3[CH2:41][CH2:40][N:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[OH:51])[CH2:44][CH2:43]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (462 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]3[O:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[CH:46]=3)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH3:25])=[CH:15]2)=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[ClH:53].[OH:54][CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1.C([O-])(=O)C.[Na+]>C(Cl)(Cl)Cl>[ClH:53].[OH:54][CH:55]1[CH2:59][CH2:58][N:57]([CH2:1][C:3]2[CH:52]=[CH:51][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[CH:46]=4)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:29])[CH3:25])=[CH:15]3)=[O:13])=[O:8])=[CH:5][CH:4]=2)[CH2:56]1
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reactant: OC1CCNC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(CN3CCC(O)C3)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reaction time: 0.33 h
Yield: 49 %

Procedure:
NaHB(OAc)3 (0.085 g, 0.4 mmol, 1.4 eq.) was added in three equal portions in 10 minutes to a cloudy solution of compound 19 (0.2 g, 0.285 mmol), 3-hydroxypyrrolidine hydrochloride (0.07 g, 0.57 mmol, 2.0 eq.) and sodium acetate (0.047 g, 0.57 mmol, 2.0 eq.) in dry chloroform (10 mL) under N2 in an ice bath. The reaction was stirred in ice bath for 20 minutes and at room temperature for 4 hours to give a white suspension. The reaction mixture was worked up and purified as above to give compound 20h (0.113 g, 51%) as a white foam.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([NH2:12])=[O:11].N1(C2C=CN=CC=2)CCCC1>CN1CCCC1=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]([NH2:12])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: NC=O
Reactant: N#Cc1ccc(Cl)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(C(N)=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.127 g of bis(tricyclohexylphosphine)-palladium, 2.377 g of 4-chlorobenzonitrile, 3.12 g of formamide, 2.82 g of 4-pyrrolidinopyridine and 20 ml of 1-methyl-2-pyrrolidinone are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, the white precipitate is filtered and mixed with ethyl acetate and water, and extracted. The aqueous phase is extracted by shaking 3 times with ethyl acetate, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 40% (part of the product remains in the water phase).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][OH:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a gray solid. Mass spectrum (ESI, [M+H]+) m/z 296. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.45 (d, 2H, J=7.33 Hz), 7.38 (t, 2H, J=7.49 Hz), 7.30 (d, 1H, J=7.20 Hz), 7.24 (d, 1H, J=8.71 Hz), 7.08 (s, 1H), 6.81 (dd, 1H, J=8.70 and 1.45 Hz), 6.34 (s, 1H), 5.13 (s, 2H), 5.06 (s, 2H), 2.04 ppm (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OC(=O)C)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][CH:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)Nc1nc2ccc(CCBr)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(CCN3CCC(Cc4ccccc4)CC3)cc2s1
Yield: 67 %

Procedure:
A solution of 3 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethane and 1.95 g of 4- benzylpiperidin and 3.5 g of K2CO3 in 20 ml of DME was heated at 75° C. for 2 hours. The solution was diluted with ethylacetate and washed with brine, after removal of the solvent the residue was heated at reflux in 50 ml of ethanol containing 5 ml of 5 M NaOH for 1 hour. The solvent was evaporated and the residue taken up in ethylacetate was washed with brine and dried. After removal of the solvent, the reaction produce was chromatographed on silica gel eluting with ethylacetate/cyclohexane ⅓ affording the title compound in 67% yield, m.p. 152-153° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](OCC2C=CC=CC=2)=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CO)nn2Cc1ccccc1
Yield: 104.4 %

Procedure:
To a solution of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate (17.7 g; 0.05 mol), diethyl ether (100 ml) and tetrahydrofuran (THF) (170 ml) stirred at room temperature was slowly added LiAlH4 (3.8 g; 0.1 mol). Once the addition was complete, the suspension was stirred at reflux for 24 hours. The reaction was stopped by destroying the excess LiAlH4 via addition of water (40 ml) and 5N NaOH (10 ml). The organic phase was separated out and the solvent was evaporated off under reduced pressure. The crude residue obtained was purified by crystallization from 95° ethanol to give 14 g of (1-benzyl-5-methoxy-1H-indazol-3-yl)methanol with a melting point of 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(CCC(O)Cc2cccc(Cl)c2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 81.1 %

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[4-(3-chloro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.53 g, 5.71 mmol) was reacted with tert-butyidimethylsilyl chloride (0.97 g, 6.4 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-chloro-phenyl)-butyl]-pyrrolidin-2-one (1.77 g). 1H NMR (CDCl3) δ7.16 (m, 3H), 7.01 (m, 1H), 5.61 (d, 1H), 3.83 (m, 1H), 3.58 (m, 1H), 2.68 (m, 2H), 2.28 (m, 3H), 1.73-1.36 (m, 5H), 0.84 (s, 9H), −0.05 (s, 3H), −0.2 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Br-].[CH2:61]([O:63][C:64](=[O:69])[CH2:65][CH2:66][CH2:67][Zn+])[CH3:62].[Cl-].[NH4+]>O1CCCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:61]([O:63][C:64](=[O:69])[CH2:65][CH2:66][CH2:67][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1)[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Reactant: CCOC(=O)CCC[Zn+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
The 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (100 mg, 0.201 mmol) obtained in Step 2 of Example 383 was dissolved in tetrahydrofuran (1.5 mL). Thereafter, palladium diacetate (10.0 mg, 0.045 mmol), S-Phos (33.0 mg, 0.080 mmol), and 4-ethoxy-4-oxobutylzinc bromide (0.5 M tetrahydrofuran solution, 0.5 mL) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at room temperature for 14 hours. Thereafter, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-ethoxy-4-oxobutyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (75.2 mg, 70%.) in the form of a white solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH3:24])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CC(=O)OCC>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:20][C@H:19]1[CH3:24])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1ncsc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncsc1N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 120 °C
Reaction time: 7 h
Yield: 30.8 %

Procedure:
To a solution of methyl 5-bromo-1,3-thiazole-4-carboxylate (3 g) in NMP (30 mL) was added (R)-1-N-Boc-2-methylpiperazine (2.76 g) followed by DIPEA (10.1 mL). The resulting solution was stirred at 120° C. for 1.5 d, at RT over weekend and at 120° C. for 7 h. After cooling down, the reaction mixture was diluted with EA and washed with sat. aq. NaHCO3, 1M HCl and sat. aq NaCl. The aq. phases were extracted with EA. The combined org. layers were dried over Na2SO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 0 for 10CV, 0 to 10 over 5CV, 10 for 5CV, 10 to 20 over 5CV, 20 for 5CV, 20 to 30 over 5CV, 30 for 5CV) to afford 1.42 g of yellow oil. LC-MS (B): tR=0.84 min; [M+H]+: 342.08.
Reaction SMILES: [C:1]([Li])(C)(C)[CH3:2].[C:6]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=O)[C:10]=2[CH:9]=1)#[N:7]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.CCCCCC>[C:6]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[CH:1][CH3:2])[C:10]=2[CH:9]=1)#[N:7]
Reactant: [Li]C(C)(C)C
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=C1c2ccccc2COc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
Suspent 23.6 gm of ethyl triphenylphosphonium bromide in 200 ml of dry tetrahydrofuran add dropwise 2.4 ml of t-butyllithium in hexane with stirring at room temperature under a nitrogen atmosphere. Continue stirring for 3 hours and then cool to -70° C. in a dry ice bath. Add 10 gm. of 2-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin in 75 ml of dry tetrahydrofuran dropwise over 30 minutes. Continue stirring at -70° C. for 30 minutes, warm to room temperature and continue stirring overnight under a nitrogen atmosphere. Pour the mixture into 400 ml. of ether, filter and wash the filtrate with saturated aqueous sodium chloride solution. Dry over anhydrous magnesium sulfate and strip to dryness. Chromatograph the residue over silica gel, eluting with 5% ethyl acetate in hexane to obtain the final product (5.73 gm).