Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:11]Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[K+]>O1CCOCC1.C(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:11][C:18]#[N:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COc1c(CCl)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1c(CC#N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a mixed solution of 5-tert-butyl-1-(chloromethyl)-2-methoxy-3-nitrobenzene (1.93 g, 7.49 mmol) in dioxane (5.0 mL), ethanol (5.0 mL) and water (2.5 mL), potassium cyanide (0.980 g, 15.0 mmol) was added, and the mixture was stirred for 2 hours under reflux. After cooling the mixture to room temperature and evaporated under reduced pressure and water was added to the residue. The resultant was extracted with ethyl acetate and then dried over anhydrous sodium sulfate, evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 1.84 g of the captioned compound (99% yield).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1cccc(C2(O)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39][C:38]#[C:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCC#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC#Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 212 mg (1 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propyn-1-ol, 248 mg (1.2 mM of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 421 mg (80%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNCCC#Cc1ccccn1
Product: Cc1ccc(C(=O)N(C)CCC#Cc2ccccn2)cc1
Yield: 35.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 4-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 31 mg of N,4-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 36%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12](=[O:25])[N:13]([CH2:21][CH2:22][CH2:23][CH3:24])[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)C1C=CC=CC=1.[C:27]([OH:30])(=[O:29])[CH3:28]>CO.[Pd]>[C:27]([OH:30])(=[O:29])[CH3:28].[NH2:10][C:11]1[C:12](=[O:25])[N:13]([CH2:21][CH2:22][CH2:23][CH3:24])[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CCCCn1c2c(cc(NC(=O)OCc3ccccc3)c1=O)CCCC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCn1c2c(cc(N)c1=O)CCCC2
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
(1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)carbamic acid benzyl ester (6-007) (100 mg, 0.28 mmol) was dissolved in methanol (7 mL), and to the reaction mixture were added acetic acid (16 μL, 0.28 mmol) and palladium on carbon (10%, 30 mg), and the reaction mixture was stirred vigorously under hydrogen atmosphere for 1.5 h. Palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure, and the crystalloid residue was recrystallized from hexane to give 3-amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (60 mg, 76%) as a white crystal.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].P([O-])([O-])([O-])=O.C(OCC)C>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
350 g of 1,4-dioxa-spiro[4.5]decan-8-one were suspended in 2000 ml of ethanol, and 28.1 g of sodium borohydride were added in portions while cooling with an ice bath. After stirring overnight at room temperature, first 750 ml of phosphate buffer (pH 7, Merck-Darmstadt) and then 1000 ml of diethyl ether were added, with stirring, and precipitated solids were filtered and then washed with diethyl ether. The filtrate was dried over sodium sulfate, filtered and concentrated. 345 g of 1,4-dioxa-spiro[4.5]decan-8-ol were obtained in the form of a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>N1C=CC=CC=1>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:30](=[O:31])[CH2:29][O:28][CH3:27])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A solution of 10.0 g of 11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione in pyridine is reacted analogously to Example 1(a) with methoxyacetic acid chloride, worked up, and purified, thus isolating 10.3 g of 11β,17-dihydroxy-21-methoxyacetoxy-1,4-pregnadiene-3,20-dione.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[CH2:29](C([SnH3])=C(CCCC)CCCC)[CH2:30]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[C:3](=[C:2]([CH:29]=[CH2:30])[C:11]([F:12])=[C:10]([F:13])[C:9]=2[F:14])[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6]1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(Br)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1F
Yield: 66.3 %

Procedure:
4.6 g of ethyl 5-bromo-1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 4.5 g of tributylvinylstannane and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 10 hours in 40 ml of absolute toluene under a nitrogen atmosphere. The product is filtered off with suction at room temperature, washed with water and dried. 2.7 g of the title compound are obtained (66% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH3:2].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:25])[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1cccc(Br)c1
Reactant: Cc1ccccc1[Mg]Cl
Product: CCOC(=O)C(C#N)C(c1cccc(Br)c1)c1ccccc1C

Procedure:
In analogy to example 74, step 2, from 3-(3-bromo-phenyl)-2-cyano-acrylic acid ethyl ester and o-tolylmagnesium chloride was prepared the title compound as a colorless oil, MS (ESI−): m/z=370.04 (([M−H]−), 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:16])[CH2:9][C:10](=[O:15])[CH2:11]1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2cc(Cl)ccc2F)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1CC(=O)CC(c2cc(Cl)ccc2F)C1
Yield: 72.2 %

Procedure:
A solution of 5-(5-chloro-2-fluorophenyl)cyclohexane-1,3-dione (2 g) and ammonium acetate (1.9 g) in ethanol (15 ml) was refluxed for 15 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added water (30 ml) and ethyl acetate (150 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 1-amino-5-(5-chloro-2-fluorophenyl)cyclohexan-3-one (1.45 g) as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30]([NH:29][C:25]3[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)c1
Yield: 42 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 3-tolyl isocyanate in a yield of 42%, according to the procedure for the synthesis of example 42.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[CH:2]=[CH:3][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1cc(CC(=O)O)ccc1Cl

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3-fluoro-4-(trifluoromethyl)benzonitrile and the product of example 1 step (iii).
Reaction SMILES: [I:1][CH:2]([OH:5])[C:3]#[CH:4].[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1.O>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH:2]([I:1])[C:3]#[CH:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C#CC(O)I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(I)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 500 mL 4-neck round bottom flask, equipped with a magnetic stirrer and an addition funnel, in an ice bath were placed iodopropargyl alcohol (10 g, 54.9 mmol) in THF (20 mL) and sodium hydroxide (3.4 g, 84.6 mmol) in water (20 mL) To the above cold mixture was added a solution of p-toluenesulfonyl chloride (10.4 g, 54.95 mmol) in THF (20 mL) from an addition funnel. The reaction mixture was stirred for 2 hrs. below 5° C. The reaction mixture was then poured into ice water and the precipitate was collected by suction-filtration and washed with water. After drying under vacuum, the precipitate afforded 17.2 g (yield: 93.4%) of iodopropargyl 4methylbenzenesulfonate as an off-white solid, mp=75°-78 ° C. An NMR spectrum showed the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[C:13]([NH:17][S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 30.00 g (145.17 mmol) of 2-methoxybenzenesulfonyl chloride in 150 ml of dichloromethane is admixed dropwise at 5-10° C. with 22.30 g (304.87 mmol) of tert-butylamine. The mixture is then stirred at room temperature for 2 h. Following extraction with water, the organic phase is dried over sodium sulfate and evaporated to dryness. This gives 31.10 g (88% of theory) of N-(tert-butyl)-2-methoxybenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22]5[CH:23]=[N:24][CH:25]=[N:26][CH:27]=5)=[CH:15][CH:16]=4)[C@@:11]4([CH2:31][O:30][C:29]([NH2:32])=[N:28]4)[C:10]=3[CH:9]=2)=[CH:5][CH2:4][O:3]1.CO.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:33])[CH2:7][CH:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22]5[CH:27]=[N:26][CH:25]=[N:24][CH:23]=5)=[CH:15][CH:16]=4)[C@@:11]4([CH2:31][O:30][C:29]([NH2:32])=[N:28]4)[C:10]=3[CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cncnc4)ccc2O3)=CCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cncnc4)ccc2O3)CCO1
Reaction time: 1.5 h

Procedure:
To a solution of (R)-2′-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (55 mg, 0.125 mmol) in MeOH (2 mL) palladium on carbon (66.4 mg, 0.062 mmol) was added and the mixture was hydrogenated at 50° C. (1 atm of hydrogen gas) for 30 min. Another 20 mg of Pd/C was added and hydrogenation was continued for 1.5 hr at 50° C. The mixture was filtered through a plug of celite and purified by silica gel chromatography (10-80% DCM/MeOH/NH4OH in DCM) to afford (R)-2′-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [F:1][C:2]1([F:30])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:18]3[C:26]4[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][C:13](OCC)=[O:14])=[CH:10][C:4]=2[O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[F:30][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:18]3[C:26]4[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH2:13][OH:14])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)CC(c1ccc2c(c1)OC(F)(F)O2)c1c[nH]c2c(CSC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1.67 g (3.86 mmol) of the compound from Example 103A in 8 ml of tetrahydrofuran was added dropwise to 13.5 ml (13.5 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 16 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then water and acetonitrile were added, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.39 g (92% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[CH:7][CH:3]1C(O)=O.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:3][C:2](=[O:1])[NH:10][CH:9]=2)=[N:12][CH:13]=1
Reactant: O=C(O)C1C=C(c2ccncn2)C=NC1=O
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: O=c1ccc(-c2ccncn2)c[nH]1
Reaction time: 0.5 h

Procedure:
90.8 g of 2-oxo-5-(4-pyrimidinyl)nicotinic acid was mixed with 900 ml of quinoline and then heated to reflux overnight. The mixture was then cooled and poured into 1800 ml of anhydrous ether. The mixture was stirred for 30 minutes, filtered and the solid was washed with 2 liters of ether. The solid was dried, recrystallized in 100 ml of hot dimethylformamide and dried to yield 5-(4-pyrimidyl)-2(1H)pyridone m.p. 250° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]1[CH2:28][CH:29]([OH:47])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[O:31][CH2:30][CH:29]([OH:47])[CH2:28][N:19]3[CH2:20][CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18]3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncn(Cc3ccccc3)c2c1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: OC(COc1cccc(-c2ccc3ncn(Cc4ccccc4)c3c2)c1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
A mixture of 1-benzyl-6-bromo-1H-benzo[d]imidazole (200 mg, 0.70 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (314 mg, 0.77 mmol), K2CO3 (290 mg, 2.1 mmol) and Pd(dppf)Cl2 (50 mg) in dioxane (8 mL) and H2O (2 mL) was stirred at 100° C. for 16 h. The catalyst was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to give the title compound (108 mg, 31.6%). 1HNMR (CH3OD, 400 MHz) δ: 8.43 (br, 1H), 8.25 (s, 1H), 7.75-7.68 (m, 1H), 7.59-7.48 (m, 2H), 7.33-7.10 (m, 12H), 6.95-6.89 (m, 1H), 5.46 (s, 2H), 4.52-4.46 (m, 1H), 4.43-4.32 (m, 2H), 4.12-4.01 (m, 2H), 3.57-3.47 (m, 2H), 3.40-3.25 (m, 2H), 3.19-3.04 (m, 2H). LCMS (m/z): 490.2 [M+H]+
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:69][C:70]1[CH:77]=[CH:76][C:73]([CH2:74][NH2:75])=[CH:72][CH:71]=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:29]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:75][CH2:74][C:73]3[CH:76]=[CH:77][C:70]([F:69])=[CH:71][CH:72]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 0.3 g (0.441 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 4), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.169 g (0.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.184 ml of triethylamine and of 0.11 g (0.88 mmol) of 4-fluorobenzylamine in a mixture of 4 ml of dichloromethane and 0.8 ml of acetonitrile is stirred for 48 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.232 g, 70%) after purification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10 min, 60/40 to 40/60 in 10 min and then 40/60 for 20 min gradient). [M+H+]=751.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])/[C:9]#[N:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(/C=C(\C#N)c2ccc(F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a cooled solution of (Z)-2-(4-fluorophenyl)-3-(5-methyl-2-nitrophenyl)acrylonitrile (3.0 g, 0.0106 mol) in THF (25 mL) and MeOH (75 mL) was added sodium borohydride (0.808 g, 0.0212 mol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain product as a yellow colored solid (3 g, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: NCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)NCCC(=O)O)cc1OC

Procedure:
A solution of 3.8 g of 3,4-dimethoxybenzenesulfonyl chloride in 5 ml of dioxane is added dropwise to a solution of 1.5 g of 3-aminopropionic acid in 20 ml of 1N NaOH solution. The mixture is left to stir while controlling the pH (pH>7) for 12 h, the pH is reduced below 7 by adding citric acid, and the reaction solution is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated under reduced pressure and employed without further purification in the next reaction step. The desired product is obtained with MW=289.31 (calculated); measured value (M+H)+: 290.1