Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH2:16][N:17]([C:27]3[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:29][CH:28]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:15])=[CH:9][CH:8]=2)[N:6]=1.[OH-].[Na+:41]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([CH2:16][N:17]([C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([O-:35])=[O:34])=[CH:38][CH:39]=3)[C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[O:15])=[CH:11][CH:12]=2)[N:6]=1.[Na+:41]
Reactant: CCOC(=O)COc1ccc(N(CC(=O)Nc2ccc(-c3csc(N)n3)cc2)C(=O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(OCC(=O)[O-])cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanol (30 ml) solution of ethyl {4-[N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-(4-fluorobenzoyl)amino]phenoxy}acetate (1.3 g) was mixed with 1 M sodium hydroxide aqueous solution (2.4 ml) and then stirred at room temperature overnight. After concentration of the reaction solution, the thus obtained crude product was recrystallized from ethanol to obtain 680 mg of sodium (4-[N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-(4-fluorobenzoyl)amino]phenoxy)acetate (white crystals).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[S:7].CO[CH:11](OC)[CH2:12]Br.Cl>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:11]=[CH:12][N:8]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1cccs1
Agent: Cl
Solvent: CCO
Product: c1csc(-c2nccs2)c1
Yield: 168.3 %

Procedure:
In a manner similar to Step B of Example 1, the reaction of 13.3 grams (0.027 mole) of (thien-2-yl)thiocarboxamide with 16.0 grams (0.0945 mole) of bromoacetaldehyde dimethyl acetal and 2 ml of concentrated hydrochloric acid in 250 ml of ethanol yielded 7.6 grams of 2-(thien-2-yl)thiazole as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=[CH:12][CH:13]=1
Reactant: CSc1nccc(C(Cc2ccc(F)cc2)=Nc2cccnc2Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
6.5 g (14.7 mmoles) of (2-Chloro-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethylidene]-amine is dissolved in 60 mL of dimethylformamide under nitrogen. 6.2 g of DABCO (52 mmoles) and 0.5 g of bis(triphenylphosphine)palladium dichloride are subsequently added to the reaction mixture which is stirred for 4 hours at 120° C. The cooled reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized in diethyl ether to afford 4 g of 3-(4-Fluoro-phenyl)-2-(2-methylthio-pyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a yellowish solid.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH:25]=O)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4].[NH2:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH2:25][NH:30][CH:31]4[CH2:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:32]4)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(C=O)c(F)c3)c2)n1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(CNC4Cc5ccccc5C4)c(F)c3)c2)n1
Reaction time: 1.5 h

Procedure:
A mixture of [3-(3′,5′-difluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate (67.6 g; 0.17 mol; I-X-9), 2-aminoindane (22.9 g; 0.17 mol; freebase obtained commercially) and HOAc (0.48 mL; 0.0085 mol, Note 1) in PhH (350 mL) was heated under reflux using a Dean-Stark trap to remove water. After 1.5 h, volatiles were removed in vacuo, the residue was dissolved in CH2Cl2/HOAc (400:25 mL respectively), and NaBH(OAc)3 (43 g; 0.203 mol) was added at room temperature. The mixture was stirred 12 h, and quenched by dropwise addition of water (250 mL). The mixture was stirred 30 min and separated into layers. The organic layer was washed (satd NaHCO3, brine), filtered through a pad of Na2SO4 and concentrated in vacuo. The residue was triturated with MeOH (250 mL), the resulting slurry was diluted with water (250 mL) and stirred 30 min at room temperature. Solids were collected by filtration, and washed with water. The cake was air-dried overnight on the filter, affording the title compound as an off-white solid, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (s, 9 H), 2.74 (dd, J=15.7, 6.1 Hz, 2 H), 3.09 (dd, J=15.8, 7.1 Hz, 2 H), 3.54 (quint, J=6.6 Hz, 1 H), 3.86 (s, 2 H), 6.21 (s, 2 H), 7.07-7.13 (m, 2 H), 7.15-7.21 (m, 2 H), 7.43-7.52 (m, 2 H), 7.60 (t, J=7.7 Hz, 1 H), 7.81 (ddd, J=7.9, 1.8, 1.1 Hz, 1 H), 8.06 (ddd, J=7.8, 1.3, 1.2 Hz, 1 H), 8.26 (t, J=1.7 Hz, 1 H), 8.82 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2ccccc2C(=O)O)cc1C(=O)Nc1ccncc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A100”; method 2: HPLC/MS: 1.35 min, [M+H]=390;
Reaction SMILES: [CH2:1](N)[CH2:2]CC.[C:6]([N:13]1[CH:17]=[CH:16]N=[CH:14]1)([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7].O>C1COCC1>[CH2:17]([N:13]([CH3:14])[C:6]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7])[CH2:16][CH2:1][CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(C)C(=O)n1ccnc1

Procedure:
Butylamine (20 g, 0.23 mol) was dissolved in 100 mL of THF and added at a quick dropwise rate to a suspension of carbonyldiimidazole (37.2 g, 0.23 mol) in 200 mL of THF. The solution was headed to reflux for 3 h, then cooled, treated with 200 mL of water, and partitioned into ethyl acetate. The organic layer was separated and then washed with brine, dried with MgSO4, and then concentrated to the crude imidazolide, which was purified by distillation at 108° C. and 600 mtorr to provide a pure oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 3.40 (t, J=7.60 Hz, 2H), 3.06 (s, 3H), 1.61 (m, 2H), 1.31 (m, 2H), 0.93 (t, J=7.23 Hz, 3H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([OH:20])[C@H:10]([OH:19])[C@H:11]1[O:16][C:14](=[O:15])[C@@H:13]([OH:17])[C@H:12]1[OH:18]>>[O:15]=[C:14]1[O:16][C@H:11]([C@H:10]([CH2:9][OH:20])[OH:19])[C:12]([OH:18])=[C:13]1[OH:17]
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
The reaction mixture containing 1.0 ml of cell free extract (protein content: 10.3 mg/ml) of Gluconobacter oxydans DSM 4025as prepared in the same manner as described in Example 1-(1) and (2), 1 ml of 0.5M potassium phosphate buffer (pH 7.0) and 0.5 ml of 17.8% L-gulono-gamma-lactone was incubated at 30° C. for 17.5 hours. As a result, 2.19 g/l of L-ascorbic acid was produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:37](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:37][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccc(N6CCOCC6)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccc(N6CCOCC6)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 55.7 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-morpholin-4-ylphenyl)amine is prepared as described in Example 179a starting with 0.16 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-morpholin-4-ylphenyl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1.08 cm3 of 5N potassium hydroxide. 0.068 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-morpholin-4-ylphenyl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 391.8 %

Procedure:
A mixture of 23 g (0.0163 mol) o-fluorobenzonitrile, 70 g (0.4889 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 34 g (0.246 mol) of K2CO3, and 150 ml of acetonitrile is stirred at reflux for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give an oil. Trituration with ether furnishes 15.6 g (39%) of title compound: IR (KBr) 2200, 1590 and 1485 cm-1 ; NMR (CDCl3) δ7.65-6.9 (m, 4H), 4.02 (s, 4H), 3.33 (m, 4H), and 1.94 (m, 4H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(Cl)C(Cl)Cl.[N+](C)([O-])=O.[C:15]([OH:26])(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.S(=O)(=O)(O)O>>[OH:33][C:27]1[CH:32]=[CH:31][C:30]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([OH:26])=[O:25])=[CH:24][CH:23]=2)=[O:22])=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 30 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a mixture formed by adding 0.4 moles of AlCl3 to 0.6 mole of sym-tetrachloroethane are sequentially added, with stirring, 0.46 mole of nitromethane, 0.2 mole of terephthalic acid (reagent grade) and gradually 0.2 mole of phenol. The initial temperature of the resulting mixture is 25° C. and the temperature is raised to about 30° C. after 2 hours, then to about 40° C. after 4 hours, and about 1 hour later or until all HCl evolution is complete, the resulting mixture is allowed to stand overnight at room temperature. The mixture is treated with dilute sulfuric acid and the sym-tetrachloroethane is distilled from the mixture. The recovered solid is redissolved in boiling 10% Na2CO3, filtered, reprecipitated with concentrated HCl, and finally washed with water. About a 50% yield of 4-(4-hydroxybenzoyl) benzoic acid of good purity is obtained.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.CO[C:13](=[O:33])[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:15][N:16]([CH3:18])[CH3:17]>C(OCC)C>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:14]([C:13]2([OH:33])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:15][N:16]([CH3:17])[CH3:18])=[CH:24][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)C(CN(C)C)c1ccc(OCc2ccccc2)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CN(C)CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Activated magnesium turnings (8 g) and a few crystals of iodine were charged to diethyl ether (200 ml). After addition of 1,5-dibromopentane (20.7 ml; 0.15 mol), the reaction mixture was refluxed for 2 hours. The reaction mass was cooled to 0-5° C. Separately prepared solution of 2-(4-benzyloxy-phenyl)-3-dimethylamino-propionic acid methyl ester (10 g; 0.032 mol) in diethyl ether (100 ml) was added to the above reaction mass very slowly. The temperature was raised to 25-30° C. with constant stirring for 2 hours. After completion of the reaction; the reaction mass was quenched with saturated ammonium chloride solution (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layer was washed with water (100 ml). The organic layer was dried on sodium sulphate, concentrated under reduced pressure and the product was isolated in n-heptane (25-30 ml). The material was dried under vacuum at 45-50° C. Yield: 7 g, Efficiency: 62%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9]
Reactant: CC1(C)CCC(C)(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(C)(C)C1O
Temperature: 70 °C
Reaction time: 15 h
Yield: 77.7 %

Procedure:
54.9 g of 2,2,5,5-tetramethylcyclopentanone was dissolved in a solvent mixture of 95 ml of methanol and 95 ml of water, and 24.0 g of sodium borohydride was added thereto. The mixture was stirred at 70° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and 100 ml of water was added thereto. The mixture was twice extracted with 100 ml of chloroform, and the organic layers were combined and washed with 100 ml of an aqueous saturated sodium chloride solution. Then, the solution was concentrated under reduced pressure. The liquid residue was distilled under reduced pressure, whereby 43.25 g of 2,2,5,5-tetramethylcyclopentanol was obtained as a colorless oily substance (b.p. 40° C./3 mmHg).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To an ice cold solution of 1-benzhydrylazetidin-3-ol 9a (1.0 g, 4.2 mmole) in DMF (10 ml) was added 60% dispersion NaH in mineral oil (0.25 g, 6.3 mmole). After 30 min at 0° C., 5 ml more DMF was added along with methyl iodide (0.39 ml, 6.3 mmole). The ice bath was removed, and the reaction was stirred at room temperature (rt). After 1.5 hr, the reaction was poured into brine and extracted with Et2O (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting Hexanes/EtOAc (1:1) to give 919 mg (92%) of a colorless oil which crystallized on standing. 1H NMR (DMSO-d6) δ7.42 (4H, d, J=7.3 Hz), 7.27 (4H, t, J=7.3 Hz), 7.13 (2H, t, J=7.3 Hz), 4.39 (1H, s), 3.95 (1H, p, J=5.8 Hz), 3.35 (2H, t, J=6.3 Hz), 3.11 (3H, s), 2.75 (2H, t, J=5.6 Hz).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[F:57][C:58]1[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:59]=1[CH2:60][CH:61]1[CH2:66][N:65]([CH3:67])[CH2:64][CH:63]([NH2:68])[CH2:62]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:68][CH:63]3[CH2:62][CH:61]([CH2:60][C:59]4[C:69]([F:73])=[CH:70][CH:71]=[CH:72][C:58]=4[F:57])[CH2:66][N:65]([CH3:67])[CH2:64]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1CC(N)CC(Cc2c(F)cccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(Cc2c(F)cccc2F)CC(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g, 2.07 mmol) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of 5-(2,6-difluorobenzyl)-1-methylpiperidin-3-amine (511 mg, 2.13 mmol) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was progressed to the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1[Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2c(N)cc(=O)n(C3CCC3)c2n1
Solvent: ClCCl
Product: CSc1ncc2c(N)c(Br)c(=O)n(C3CCC3)c2n1
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a mixture of 5-amino-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.3 g, 4.46 mmol) in DCM (120 mL) at 0° C. was added N-bromosuccinimide (0.87 g, 4.9 mmol) in 5 portions over 5 min. After stirring for 30 min, the DCM was evaporated under reduced pressure and the residue treated with 100 mL water and 100 mL NaHCO3 (sat'd, aq). The crude product was extracted into EtOAc (2×100 mL). The combined organic layers were washed with NaHCO3 (4×60 mL) and water (2×50 mL) and evaporated under reduced pressure to give 1.3 g of 5-amino-6-bromo-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:11][CH2:12][CH2:13][CH:14]([OH:33])[CH2:15][CH2:16][CH:17]([OH:32])[CH2:18][CH2:19][CH2:20][C:21]([CH3:31])([CH3:30])[CH2:22][O:23]C1CCCCO1)[CH2:3][O:4]C1CCCCO1.S(=O)(=O)(O)O>CO>[CH3:30][C:21]([CH3:31])([CH2:20][CH2:19][CH2:18][CH:17]([OH:32])[CH2:16][CH2:15][CH:14]([OH:33])[CH2:13][CH2:12][CH2:11][C:2]([CH3:1])([CH3:34])[CH2:3][OH:4])[CH2:22][OH:23]
Reactant: CC(C)(CCCC(O)CCC(O)CCCC(C)(C)COC1CCCCO1)COC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)(CO)CCCC(O)CCC(O)CCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A solution of 2,2,13,13-tetramethyl-1,14-bis(tetrahydropyran-2-yloxy)tetradecane-6, 9-diol (5.07 g, 0.01 mol) in methanol (100 mL) was treated with dilute aqueous sulfuric acid (5 mL of concentrated sulfuric acid in 15 mL of water), and stirred at room temperature overnight. The methanol was removed under reduced pressure and the residue was extracted with ethyl acetate (100 mL). The aqueous phase was saturated with solid sodium chloride and extracted again with ethyl acetate (75 mL). The combined organic extracts were washed with a saturated sodium chloride solution (50 mL) and dried over magnesium sulfate. The solid obtained after solvent removal was washed with diethyl ether (10 mL) to give 2,2,13,13-tetramethyltetradecan-1,6,9,14-tetraol (1.85 g, 58%) as a white powder. M.p.: 96-97° C. 1H NMR (300 MHz, DMSO-d6/TMS): δ (ppm): 4.42 (pseudo-t, 2H, J=5.0 Hz), 4.28 (pseudo-t, 2H, J=5.0 Hz), 3.37-3.34 (m, 2H), 3.06 (d, 4H, J=5.0 Hz), 1.47-1.08 (m, 16H), 0.77 (s, 12H). 13C NMR (75 MHz, DMSO-d6/TMS): δ (ppm): 70.1, 69.9, 38.8, 38.4, 34.9, 33.7, 24.2, 19.7. HRMS (LSIMS, nba): Calcd. for C18H39O4 (MH+): 319.2843, found: 319.2853.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.Cl.[NH:24]1[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]1>>[N:15]1[N:14]2[C:18]([N:19]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]3=[C:13]2[N:24]2[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: N#CC1CNC1
Agent: Cl
Product: N#CC1CN(c2c3c(nc4ccnn24)CCNCC3)C1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidine-3-carbonitrile hydrochloride was used as the amine.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:33]([CH:38]([CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])[OH:39])([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH:18]1([CH2:17][CH2:16][NH:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:41][CH:40]([CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[OH:39])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:14])=[CH:8][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)Cc1ccc(N(CCC2CCCCC2)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-(2-cyclohexylethylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(2-cyclohexylethylamino)phenylacetyl]tartrate as a white, crystalline solid.