Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[Li]CCCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCCC1.[Hg]>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([O-:11])(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)C2CC=C(CCO)C1C2
Agent: [Hg]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: -78 °C
Yield: 90 %

Procedure:
A dry, 2-L flask equipped with a septum inlet, magnetic stirring bar, and a reflux condenser leading to a mercury bubbler was flushed with dry nitrogen and maintained under static pressure of nitrogen. The flask was charged with 170 mL (1 mol) of (-)-nopol [[α]23D 40.2% (neat)] and 400 mL tetrahydrofuran (THF) and cooled to -78° C.. While the solution was stirring at -78° C., 455 mL (2.2 M, 1 mol) of n-BuLi was added slowly and stirred for 1 h at -78° C.; 190 g (1 mol) of p-toluenesulfonyl chloride in 200 mL of THF was added slowly and the stirring continued for another hour at at -78 C. It was then warmed to room temperature and stirred for 2 h. The reaction mixture was poured into ice-water and extracted with pentane. Evaporation of the solvent gave a thick semi-solid of nopol tosylate in 90% yield (290g). Nopol tosylate (290g) was dissolved in hot pentane (800 mL) and stored at 0° C. for 12 h to insure complete crystallization. Colorless white needles of Nopol tosylate (mp 50°-51° C.) were recovered by fast filtration in 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:33][C:34]([CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[OH:38])([CH3:36])[CH3:35]>O1CCCC1>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[C:34]([NH:33][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: COc1cccc(C(O)C(C)(C)N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C(C)(C)NC(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 65 °C
Yield: 72 %

Procedure:
A solution of 50 g. (0.26 mole) of 3,4-dimethoxyphenylacetic acid, 68 g. (0.28 mole) of EEDQ and 50 g. (0.26 mole) of α-(1-amino-1-methylethyl)-3-methoxybenzenemethanol in 450 ml. tetrahydrofuran are stirred for three days at 25° C., and then heated for 5 hours at 65° C. Tetrahydrofuran is evaporated in vacuo, and the residue is taken up with ice and 10% aqueous H2SO4 solution to pH 2. The amide is extracted twice with 500 ml. ethyl acetate. The combined organic extracts are washed with 500 ml. dilute aqueous NH4OH solution, dried (Na2SO4) and evaporated to dryness in vacuo. The residual oil is dissolved in hot diethyl ether from which it crystallizes to give 72.0 g. of impure product. Recrystallization from diethyl ether gives 70 g. (72% yield) of N-(β-hydroxy-3-methoxy-α,α-dimethylphenethyl)-3,4-dimethoxybenzeneacetamide as white crystals of analytical purity, m.p. 137°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4cccc(F)c4)C3)CC2)cc1
Yield: 27.7 %

Procedure:
The title compound (D166) (17 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-((3-fluorophenyl)amino)azetidin-1-yl)nicotinic acid (D116) (40 mg, 0.124 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (28.3 mg, 0.124 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:17])[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)[CH3:2].[OH:18][NH2:19].O>CCO.CC(O)=O>[CH2:1]([O:3][C:4]1[C:5]2([OH:17])[CH:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:19][O:18]2)[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: NO
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=NOC2(O)C(OCC)=CCCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 5.0 g (20.73 mmol) in 20 mL of EtOH and 5 mL of AcOH, 1.3 mL (20.78 mmol) of HONH2.H2O (50% wt/wt) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7) to afford 1.35 g (25% yield) as a white solid of ethyl 7-ethoxy-7a-hydroxy-3a,4,5,7a-tetrahydro-1,2-benzisoxazole-3-carboxylate
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([NH:39][C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:48])[CH2:45][CH2:44]1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Butyllithium (1.6 M in hexane, 5.0 ml, 8.00 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (3.21 g, 8.00 mmol) in THF (25 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.30 g, 5.72 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 1 h and at room temperature overnight. Water was added and the product extracted with CH2Cl2. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave trans-2-(4-tert-Butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (1.10 g).
Reaction SMILES: [Cl-:1].[NH4+].[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([CH3:15])[C:5]=1[NH:6][CH3:7].Cl>C(O)C.[Zn]>[ClH:1].[ClH:1].[NH2:12][C:10]1[CH:11]=[C:4]([CH3:3])[C:5]([NH:6][CH3:7])=[C:8]([CH3:15])[CH:9]=1
Reactant: [Cl-]
Reactant: CNc1c(C)cc([N+](=O)[O-])cc1C
Agent: Cl
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CNc1c(C)cc(N)cc1C

Procedure:
A suspension of 15.5 g of powdered zinc and 0.6 g of ammonium chloride is heated to reflux. After the source of heat has been removed, 0.02 mole (3.6 g) of 2,6-dimethyl-4-nitro-N-methylaniline is added so as to maintain reflux. At the end of the addition, the reaction mixture is filtered boiling into a solution of 0.05 mole of hydrochloric acid in 14 ml of absolute ethanol; the dihydrochloride crystallises from the filtrate. After recrystallisation from an alcohol-water mixture, a white product is obtained:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:40].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:40])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 25 (0.84 g, 1.90 mmol) in CHCl3 (9 mL) was added triethylamine (0.50 mL, 3.59 mmol) and POCl3 (1.60 mL, 17.1 mmol). After heating at reflux for 16 h, the reaction mixture was cooled to room temperature and poured onto ice and sat. aq. NaHCO3 (150 mL). The resulting mixture was extracted with CH2Cl2 (3×75 mL) and the combined organic layers dried (MgSO4). Concentration followed by flash chromatography (9:1/CH2Cl2:EtOAc) afforded 708 mg (87%) of product as a white solid, m.p. 101-103° C. 1H NMR (400 MHz, CDCl3) δ 6.10 (d, J=2.8 Hz, 1H), 6.01 (dd, J=5.6, 3.2 Hz, 1H), 5.92 (t, J=6.0 Hz, 1H), 5.42 (s, 2), 4.97 (dd, J=11.6, 3.6 Hz, 1H), 4.32 (m, 1), 4.21 (dd, J=12.0, 5.2 Hz, 1H), 2.12 (s, 6H), 2.06 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C:25]([CH3:37])([CH3:36])[C:26]#[C:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1>CC(O)C.C([O-])(=O)C.[NH2+]1CCCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][C:27]#[C:26][C:25]([OH:24])([CH3:37])[CH3:36])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(O)C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (400 mg) in 2-propanol (10 mL) were added a solution of 4-[(4-hydroxy-4-methylpent-2-yn-1-yl)amino]-1,3-thiazol-2(5H)-one (365 mg) in 2-propanol (5 mL) and piperidinium acetate (175 mg). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (540 mg).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH3:23])[N:14]=[N:15][CH:16]=1>>[ClH:10].[CH3:23][C:19]1[N:18]([CH2:17][C:13]2[N:14]=[N:15][CH:16]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1ccccc1
Product: Cc1nccn1Cc1cc(-c2ccccc2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=251.2 (M+H+), was prepared from phenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9].[N:33]1([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:34][CH2:35]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9]
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1OC
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1OC

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3,4-dimethoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:12]1[C:13]2[N:14]([N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=1)[CH2:10][CH3:11].O>CS(C)=O>[CH3:20][O:19][CH2:18][C:15]1[N:14]2[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:13]2[C:12]([C:9](=[O:8])[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: CCC(O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Triethylamine (7.56 mL) was added to a solution of the compound of Example 328 (1.55 g) in dimethylsulfoxide (60 mL). While the solution was stirred at room temperature, sulfur trioxide-pyridine complex (4.28 g) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, water (300 mL) was added. The resulting crystals were collected by filtration and thoroughly dried to afford the title compound as a colorless powder (1.49 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added N,N-dimethylcarbamoyl chloride (3.2 μL, 0.034 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired compound as TFA salt (3.4 mg, 30%) as TFA salt. LCMS calculated for C20H28N5O2S (M+H)+: m/z=402.2. Found: 402.2.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S-:13].[Na+].O>CN(C)C=O>[CH3:12][S:13][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Nc1nc2cccc(Br)n2n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccc2nc(N)nn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (20 g, 93.9 mmol) in dimethylformamide (60 mL) was added sodium thiomethoxide (8.60 g, 122 mmol) portionwise, and the reaction mixture was stirred at 60° C. for 2 hours. The mixture was allowed to cool, water added (350 mL) and the product collected by filtration to afford the expected compound as a white solid. No further purification was required. Yield: 15.7 g, 93%; LCMS method: 3, RT: 1.38 min, MI: 181 [M+1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:29]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C(CCOCCO)c1ccc(Cc2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCOCCC(=O)c1ccc(Cc2cccnc2)cc1
Yield: 85.7 %

Procedure:
In 30 ml of methylene chloride were dissolved 3.0 g of 3-[p-[3-(2-hydroxyethyl)oxypropionyl]benzyl]pyridine and 1.61 ml of triethylamine, and into the resulting solution was dropped 0.90 ml of acetyl chloride over 30 minutes with ice-cooling. The resulting mixture was subjected to reaction at room temperature for 2 hours, after which 20 ml of water was added to the reaction mixture. The pH of the mixture was adjusted to 7 with sodium hydrogencarbonate, and the organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 2.94 g (yield 85.7%) of pale yellow, oily 3-[p-[3-(2-acetoxyethyl)oxypropionyl]benzyl]pyridine.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(O)COc1ccc(C#N)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100%) EtOAc/DCM as eluent to give 4-(2-hydroxy-2-methyl-propoxy)benzonitrile (3.0 g, 94%) as a yellow solid. ESI-MS m/z calc. 191.1, found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]([OH:22])([CH3:21])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:21][C:2]([O:22][Si:31]([CH3:33])([CH3:32])[CH3:30])([CH3:1])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O[Si](C)(C)C
Temperature: 12.5 °C

Procedure:
2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5.0 gm) is dissolved in methylene chloride (25 ml) at 25-30° C., triethylamine (2.5 gm) is added and then the contents are cooled to 10-15° C. under N2 atmosphere. Trimethylsilyl chloride (2.5 gm) is slowly added to the reaction mass while maintaining the temperature 10-15° C., the mass temperature is raised to 25-30° C. and maintained for 2 hours at the same temperature to give the reaction mass of 2,N-dimethyl-2-(trimethylsilyloxy)-N-(3,3-diphenylpropyl)-1-propanamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[N:10]=C(C#N)[CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:3]1.[OH-:27].[Na+].Cl.[CH2:30]([OH:32])[CH3:31]>O>[CH3:1][C:2]1([CH3:26])[C:11]2[N:10]=[C:31]([C:30]([OH:27])=[O:32])[CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:3]1
Reactant: CCO
Reactant: [OH-]
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C#N)nc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)nc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a stirred mixture solution of 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (698.0 mg, 2.0 mmol) in ethanol (10.0 mL) was added 50% sodium hydroxide in water (8.5 mL). The reaction mixture was stirred at 90° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (660.6 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=368.1.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:13][C:7](=[O:12])[CH2:8][C:9]1([CH3:11])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH3:15]
Reactant: CC(O)CCS
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(C)OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 7.14 grams (0.055 moles) ethyl acetoacetate is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent by means of rotary evaporation. 9.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions:
Reaction SMILES: N.[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:22]=2)[NH:17][CH:16]=1.C[N:37](C)C=O>O>[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH2:37])=[O:26])[CH:22]=2)[NH:17][CH:16]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Ammonia (0.88, 0.2 ml) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl]-1H-indole-5-carboxylic acid, 4-nitrophenyl ester (0.3 g) in warm (50° C.) dimethylformamide (3 ml). The mixture was stirred at 50° C. for 4 hours., poured into water (40 ml) and stirred for a further 0.5 hours. The precipitate (0.21 g) was collected and crystallised from ethanol to give the title compound (0.12 g) as an off-white solid m.p. 254°-6° C. T.L.C. Silica, Ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.75.