Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([N+:12]([O-])=O)[C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2].Cl[Sn]Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([F:15])[C:11]([NH2:12])=[C:6]2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2]
Reactant: CCN1c2ccc(F)c([N+](=O)[O-])c2CS1(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1c2ccc(F)c(N)c2CS1(=O)=O
Reaction time: 12 h
Yield: 74.3 %

Procedure:
A mixture of 1-ethyl-5-fluoro-1,3-dihydro-4-nitro-2,1-benzisothiazole 2,2-dioxide (1.0 g, 3.8 mmol) and SnCl2.H2O (4.34 g, 19.2 mmol) in ethyl acetate (50 mL) was heated at reflux for 3 h. After completion of the reaction based on thin layer chromatography, the mixture was diluted with ethyl acetate (100 mL) and solid Na2CO3 (12.5 g) was added. The resulting mixture was vigorously stirred for 12 h and then filtered through a pad of diatomaceous earth (Celite®). The filtrate was then evaporated under reduced pressure, and the residue was subjected to flash chromatography (silica gel, chlorobutane:ether 1:10 v/v) to give 650 mg of the title compound of Step D. 1H NMR (CDCl3, 400 MHz): δ 6.94 (m,1H), 6.08 (m,1H), 4.10 (s,2H), 3.80 (br s,2H), 3.62 (q,2H), 1.36 (t,3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([CH2:48][NH2:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:42]1([CH2:48][NH:49][C:15]([C:12]2[CH:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[O:14][N:13]=2)=[O:17])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCCC1)c1cc(-c2ccc3[nH]ncc3c2)on1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A), was dissolved in N,N-dimethylformamide (0.8 mL) followed by the addition of HATU (60 mg, 0.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL). Then a solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved in N,N-dimethylformamide (0.8 mL) was added, followed by diisopropylethylamine (56 μL, 0.31 mmol) dissolved in N,N-dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91-0.97 (m, 2H), 1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H), 7.22-7.24 (m, 1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m, 1H), 8.38-8.41 (m, 1H). MS (ESI+) m/z 325 (M+H)+; (ESI−) m/z 323 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1sc(CCC2CC2)cc1N
Reaction time: 5 h

Procedure:
A suspension of 5-cyclopropylethynyl-3-nitrothiophene-2-carboxylic acid methyl ester (1.0 g) and palladium (5% on carbon) (170 mg) in methanol (50 mL) was vigorously stirred under an atmosphere of hydrogen at atmospheric pressure for 5 h. The catalyst was then filtered off through kieselguhr, and the solvent was removed in vacuo. The product with the molecular weight of 225.31 (C11H15NO2S) was obtained in this way; MS (ESI): 226 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.C(O)(C)C>CC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:21])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A stirred solution of (9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracene-9-carboxaldehyde prepared as in Example 1i (290.5 g, 1.14 moles) dissolved in acetone (5.0 L) was cooled to 10° C. and treated with Jones Reagent (950 ml, ~ 1.19 moles) over a period of 1 h. The reaction mixture was stirred overnight at room temperature, then analyzed by TLC [silica gel/methylene chloride:hexane (1:1)]. Conversion of the aldehyde (Rf =0.50) to the desired carboxylic acid (Rf =0.0-0.15) was shown to be complete. Isopropanol (150 ml) was added, and the mixture stirred for another 3 h to quench any excess Jones Reagent. The acetone supernatant was decanted away from the green-black sludge that had formed, and the sludge was washed with acetone (2×1 L). The combined acetone solutions were concentrated on the rotary evaporator to a volume of 1.5 L, then poured into ice/water (6 L) with vigorous stirring. A yellow-white gum precipitated and gradually solidified with continued stirring. The solid was collected by filtration, pulverized to a fine off-white powder in a mortar & pestle, then rewashed with cold water (2×1 L). Vacuum drying afforded the title compound as an off-white powder (304.8 g, 98.7%), mp 175°-178° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].CCO>C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])=[CH:12][CH:11]=1)=[C:15]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)[C:16]([CH3:26])=[CH:17]2
Reactant: CCOC(=O)C=Cc1ccc(Oc2c(-c3ccsc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(C=CC(=O)O)cc3)c(-c3ccsc3)c(C)cc2c1
Temperature: 60 °C
Yield: 98.4 %

Procedure:
A solution containing 3-[4-(6-Methoxy-3-methyl-2-thiophen-3-yl-naphthalen-1-yloxy)-phenyl]-acrylic acid ethyl ester (201) (0.27 g, 0.61 mmol), 1 N NaOH (5 mL), EtOH (4 mL), THF (4 mL) was heated at 60° C. for 2.5 h. Reaction mixture was cooled to room temperature and quenched with 20% HCl then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified with 1.5% to 3.5% MeOH in DCM over 30 min to give 0.25 g (99%) of the title compound (202) as a white foam. 1H NMR (400 MHz, d-CDCl3): δ 2.31 (s, 3H), 3.92 (s, 3H), 6.24 (d, J=16 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 6.90-6.92 (m, 1H), 7.02-7.05 (m, 2H), 7.12 (m, 1H), 7.21-7.23 (m, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.56 (m, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH:9](=O)[CH2:10][CH3:11].[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:9][CH2:10][CH3:11]
Reactant: CN(C)CCCCN
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCCCCN(C)C
Reaction time: 0.33 h

Procedure:
A solution of N1,N1-dimethylbutane-1,4-diamine (0.64 g, 5.5 mmol) and propionaldehyde (0.38 mL, 5.2 mmol) in 20 mL methanol was stirred at rt overnight. Sodium borohydride (0.31 g, 8.3 mmol) was added and the reaction mixture was stirred for 20 min. The reaction was quenched with 1N NaOH, extracted with ether and washed with brine. Drying, solvent evaporation and flash chromatography (0-12% [10% NH4OH/MeOH]/CH2Cl2) gave N1,N1-dimethyl-N4-propylbutane-1,4-diamine. 1H NMR (CDCl3) δ 2.61 (t, J=6.7 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.21 (s, 6H), 1.49 (m, 6H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]([NH2:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[C:13]([NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[F:1])([CH3:15])([CH3:14])[CH3:12]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)(C)C)c1F
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzoic acid (8.76 mmol, 1.35 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution in ethyl acetate). The reaction was stirred for 2 hours and diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under reduced pressure to yield the title compound (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19](=[O:28])[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19](=[O:28])[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)(=[O:39])=[O:38]
Reactant: Cc1cc(C)cc(C(=O)c2nccn2CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)c2nccn2CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)c1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butan-1-ol (0.63 g) (see Preparation 47) and triethylamine (0.20 g) were dissolved in dichloromethane (12 ml), cooled in an ice-bath and methanesulphonyl chloride (0.19 g) added. The mixture was stirred for 30 minutes, dichloromethane (35 ml) added and the solution washed sequentially with water (2×30 ml) and brine (30 ml). The organic phase was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was dissolved in acetonitrile and the solvent removed under reduced pressure to give 1-methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]-butane (0.72 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 2-fluoropyridine-3-carbonyl chloride (3.2 g, 20 mmol, Step D) and NaHCO3 (4 g, 48 mmol) in CH2Cl2 added in dropwise a solution of 4-tert butylaniline (3.0 g, 20 mmol). After the addition, the suspension was stirred at RT for 5 h. Solid inorganic salts were removed via filtration. The filtrate was concentrated to afford a brown solid as desired compound. MS: 273 (M+H). Calc'd. for C16H17FN2O—272.33.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][N:28]3[CH2:29][CH2:30][CH:25]([C:21]4[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=4)[CH2:26][CH2:27]3)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2c(c1)OCCCO2
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)OCCCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.Cl>C(O)C.C(N)(C)C>[CH:6]([NH:7][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1)([CH3:8])[CH3:5]
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: Cl
Solvent: CC(C)N
Solvent: CCO
Product: CC(C)Nc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 30 ml of ethanol, 4.26 ml of isopropylamine was added, and the mixture was heated for 44 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.36 g of the desired compound as pale yellow needles, m.p. 272°-274 ° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[C:3]([F:9])[C:4]([O:6]CC)=O.[Cl:17][C:18]1[C:23]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]([N:28]=[C:29]=[O:30])=[C:20]([F:31])[CH:19]=1>>[Cl:17][C:18]1[C:23]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:22][C:21]([N:28]2[C:4](=[O:6])[C:3]([F:9])=[C:2]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[NH:1][C:29]2=[O:30])=[C:20]([F:31])[CH:19]=1
Reactant: CCOC(=O)C(F)=C(N)C(F)(F)C(F)(F)F
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4,4,5,5,5-hexafluoro-2-pentenoate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 160°-162° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([C:14]#N)[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:28])C>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH:14]=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2cc(Cl)ccc2Cl)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CC1(c2cc(Cl)ccc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of 1-(2,5-dichloro-phenyl)-cyclopentanecarbonitrile (198) (32 g, 133.891 mmol) in dichloromethane (350 mL), was added Diisobutylaluminiumhydrid (25% in toluene, 191.0 mL, mmol) for 1 h at −70° C. and the reaction mixture was stirred 2 h at the same temperature (silica TLC, 10% ethyl acetate in hexane, Rf=0.7) The reaction mixture was quenched with saturated potassium sodium tartarate solution very slowly and stirred at room temperature for 16 h. It was extracted with dichloromethane, washed with brine and dried, concentrated to get the crude residue which was purified over nor mal silica gel (100-200 mesh) column chromatography using gradient eluent 2-20% ethyl acetate in hexane to get 1-(2,5-dichloro-phenyl)-cyclopentanecarbaldehyde (199) (25 g, 76.8%), as colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (0.5 g, 1.97 mmol) in DMF (10 mL) was added NaH (80 mg, 1.97 mmol) and the suspension was stirred for 20 minutes under nitrogen. This was followed by the addition of (3-bromopropoxy)(tert-butyl)dimethylsilane (457 μL, 1.97 mmol) and the reaction mixture was heated to 100° C. under nitrogen overnight. The solvent was removed to yield crude 4-(5-(4-fluorobenzyl)-1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-pyrazol-3-yl)pyridine that was taken into THF (10 mL) at 0° C. and TBAF (1 M in THF, 1.97 mL, 1.97 mmol) was added. The mixture was stirred at 0° C. for 1 hour followed by stirring at room temperature for 1 hour. The solvent was removed and the residue was diluted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (2-5% MeOH/CH2Cl2) then again using 3% MeOH/EtOAc followed by trituration with Et2O to yield the title compound as a white solid (0.33 g, 54%). 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.55 (d, 2 H), 7.60 (d, 2 H), 7.16-7.24 (m, 2 H), 7.04 (t, 2 H), 6.40 (s, 1 H), 4.18 (t, 2 H), 4.03 (s, 2 H), 3.57 (t, 2 H), 1.87-1.96 (m, 2 H); m/z (APCI+) for C18H18N3FO 312.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:10][C:8]([F:9])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccc(C(F)(F)F)cn1)c1ccccc1
Yield: 66.4 %

Procedure:
A solution of 2-hydroxy-5-(trifluoromethyl)pyridine (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.59 g, 66% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CNCC=CC#CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Yield: 88.4 %

Procedure:
N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (1.06 g; 7.04 mmol) and potassium carbonate (1.95 g; 14.1 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (1.31 g; 6.15 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. After completion of addition, the mixture was removed from the ice bath, and stirred for 15 minutes at room temperature. Reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform), to thereby yield 1.54 g of the target compound (yield: 88.4%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[CH3:15][O:14][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([C:26]3[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2s1

Procedure:
Crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (60 mg) was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester via general procedure A with to get 55 mg 104 following reverse phase HPLC purification. MS (Q1) 388.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][OH:7])=[O:4].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:9]([NH:8][C@@H:5]([CH2:6][O:7][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([O:2][CH3:1])=[O:4])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](COc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.8 g of trt-Ser-OMe (Bachem), 0.75 of phenol, and 2.25 g of triphenylphosphine were dissolved together in 60 ml of THF, absolute, and treated dropwise with 1.49 g of diethyl azodicarboxylate at 0° C. in the course of 30 min. The reaction mixture was stirred at 0° C. for 30 min and warmed to RT (about 1 h). For working-up, the solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel (heptane/ethyl acetate=1.5/1). The methyl (S)-2-tritylamino-3-phenoxypropionate thus obtained crystallized slowly in long needles, and was heated under reflux for 1 h in 5 M HCl to remove the protective groups. The reaction solution was evaporated to dryness under reduced pressure by coevaporating a number of times with toluene and the residue was recrystallized from a little tert-butanol.