Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a solution of 4-(4-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (80 mg, 67%).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([NH:20][C@H:21]([C:29](O)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([NH:20][C@H:21]([C:29]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCc1cccc2ccccc12
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1cccc2ccccc12
Yield: 78.3 %

Procedure:
In substantially the same manner as Working Example 2, 1-naphthalenemethylamine (4.32 g) was condensed with Boc-L-phenylalanine (6.63 g) to give N-(Boc-L-phenylalanyl)-1-naphthalenemethylamine (7.92 g) (yield 91%). The Boc group of the product was deprotected in substantially the same manner as Working Example 91 to give N-(L-phenylalanyl)-1-naphthalenemethylamine hydrochloride (4.24 g) (yield 64%). The compound thus obtained (0.75 g) was condensed, in substantially the same manner as Working Example 8, with monoethyl ester of (2S,3S)-N-benzylaziridine-2,3-dicarboxylic acid (0.50 g) obtained in Working Example 95 to give the above-titled compound (Compound 99; 0.79 g) as white crystals (yield 74%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1.[C-:28]#[N:29].[Na+]>CN(C)C=O.ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:28]#[N:29])=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C

Procedure:
Heat a solution of 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (0.42 g; 1.0 equiv; 1.09 mmoles) and and sodium cyanide (0.085 g; 1.6 equiv; 1.73 mmoles) in dimethylformamide (3 mL) to 100° C. for 2 hours. Cool the mixture to ambient temperature, dilute with dichloromethane (20 mL) and wash the reaction mixture with water (25 mL). Extract the aqueous layer with dichloromethane (2×20 mL). Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford crude product. Combine the crude product and purify by column chromatography (0 to 10% methanol in dichloromethane) to afford 3-cyanopropyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as a light brown oil and used in next step. MS (m/z): 378 (M+1).
Reaction SMILES: [CH:1]([CH:14]1[C:19](=[O:20])[CH:18]2[CH2:21][CH2:22][N:15]1[CH2:16][CH2:17]2)([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.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[CH:1]([C@H:14]1[C@@H:19]([OH:20])[CH:18]2[CH2:17][CH2:16][N:15]1[CH2:22][CH2:21]2)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
398.0 mg (1.30 mmol) of a racemic mixture of 2-benzhydrylquinuclidin-3-one (1-2), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 6.4 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by degassing and stirring for 30 minutes at room temperature. 0.13 mL (0.13 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 18 hours at 20 to 25° C. at a hydrogen pressure of 1 MPa. The same post-treatment procedure as Example 7 was carried out to obtain (2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2) at a yield of 97% and optical purity of >99% ee.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]([NH:37][CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:35][CH:34]([N:37]([CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=1)[CH:38]([CH3:40])[CH3:39])[CH3:36]
Reactant: CC(C)NC(C)C
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)C(C)C
Temperature: 140 °C
Yield: 64.4 %

Procedure:
A 5-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.200 g, 0.378 mmol, Intermediate B) diisopropylamine (0.077 g, 0.757 mmol), potassium carbonate (0.105 g, 0.757 mmol), in 3 mL of MeCN. The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (40 g of silica gel, 10 to 40% EtOAc in hexanes) to afford 2-(4-((2S)-2-((bis(1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.130 g) as
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH:16]1[CH2:17][CH2:18][CH2:19][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([NH:4][CH2:3][CH:2]([CH3:27])[CH3:1])=[O:6])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1
Reactant: CC(C)CNC(=O)C1CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)C1CCN(C2CCCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (1.95 g, 5.1 mmol) was dissolved in DCM (16 mL) and TFA (4 mL) was added. The reaction mixture was stirred at rt for 2 h under nitrogen, then the solvents were removed in vacuo, to give 1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt (2.02 g), Intermediate 5, as a dark yellow oil which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH:26](O)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[CH:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=CN3c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (100 mg, 0.27 mmol) (from Example 6, Step B supra) in formic acid (5 mL) was heated at 110° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 86 mg, 83%).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])=[O:17]>C1CCCCC1.C(Cl)Cl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])=[O:17]
Reactant: COc1c(C)c(C(=O)c2ccccc2F)c(OC)c2ccccc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COc1c(C)c(C(=O)c2ccccc2F)c(O)c2ccccc12

Procedure:
(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluorophenyl)methanone LJ103 (75 mg, 0.231 mmol) was treated according to general procedure 12.1. The product was obtained as a yellow powder. Rf(Cyclohexane:DCM 3:2)=0.29. Yield=68 mg (94%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11](C2OC=CC=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:39]2[CH:40]=[CH:41][S:37][CH:38]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1H) 7.93 (d, J=2.94 Hz, 1H) 7.87 (d, J=7.72 Hz, 1H) 7.53-7.75 (m, 6H) 7.49 (t, J=6.25 Hz, 1H) 7.39 (d, J=2.57 Hz, 1H) 6.57 (s, 1H) 5.68 (dd, J=7.91, 2.02 Hz, 1H) 4.19 (d, J=5.15 Hz, 2H) 3.47 (s, 2H) 3.21 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrBr.[CH3:7][O:8][C:9]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:10]>CO>[C:2]([S:1][C:14]1[CH:15]=[C:11]([C:9]([O:8][CH3:7])=[O:10])[N:12]([CH3:16])[CH:13]=1)#[N:3]
Reactant: COC(=O)c1cccn1C
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(SC#N)cn1C
Temperature: 25 °C
Yield: 47.6 %

Procedure:
Potassium thiocyanate (6.44 g, 66 mmol) is suspended in 18 ml of methanol and cooled to -78° under nitrogen. A solution of 1.75 ml of bromine (33 mmol) in 10 ml methanol is added dropwise. The resulting light yellow suspension is stirred for an additional 5 minutes at -78° before 4.17 g (30 mmole) of 2-methoxycarbonyl-1-methylpyrrole in 5 ml methanol is added all at once. After stirring and gradual warming to room temperature, the reaction mixture is poured into 250 ml of ice water, stirred vigorously and filtered. The solid is washed with water, dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white solid which after recrystallization from hexane-ethyl acetate gives 2.8 g of pure 4-cyanothio-2-methoxycarbonyl-1-methylpyrrole.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:42][C:43]([O:45][CH3:46])=[O:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:46][O:45][C:43](=[O:44])[CH:42]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH3:14]
Reactant: CCNc1cc(F)ccc1C(=O)N(C)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide (0.23 g, 1.02 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.51 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was reacted with methyl (triphenylphosphoranylidene)acetate (375 mg, 1.12 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.13 g, 57%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cccc(CC)c2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
7-Ethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (76.6 g, 0.24 mol) was dissolved in 450 mL dichloromethane and cooled to 0° C. Trifluoroacetic acid (150.0 mL, 1.96 mol) was added within 30 min. and after an additional 45 min. the reaction mixture was concentrated at a rotary evaporator. The residue was dissolved in 300 mL dichloromethane and poured cautiously onto 500 mL saturated aq. sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was suspended in 400 mL n-hexane and put in an ultrasonic bath for 15 min. The suspension was filtered and the filter cake was washed with 100 mL n-hexane. This procedure was repeated to give the desired product as a light brown solid (40.2 g, 76.6%). EI-MS: m/e 217.1 ([M]).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[N:13]1([C:19](=[O:21])[CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:7]([Cl:10])=[O:6])[CH2:15][CH2:14]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (2.31 g, 7.80 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-piperazin-1-yl-ethanone (2.0 g, 15.6 mmol) and pyridine (1.38 ml, 17.2 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 1.12 g (38%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[N:35]=1>O1CCCC1>[Br:33][C:34]1[N:35]=[C:36]([CH2:40][N:9]2[C:10]3[C:15](=[CH:14][C:13]([F:18])=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:37]=[CH:38][CH:39]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(F)cc3c2=O)cc1C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a solution of 0.050 g (0.169 mmol) of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 4tt in 1.0 mL of tetrahydrofuran was added 0.4 mL (0.5 M in toluene, 0.203 mmol) of potassium hexamethyldisilazide and the reaction solution was stirred for 5 min, followed by the addition of 50.9 mg (0.203 mmol) of 2-bromo-6-bromomethyl-pyridine in 0.5 ml of tetrahydrofuran. The resultant solution was stirred at 60° C. for 3 h. The reaction solution was quenched by the addition of water and the aqueous phase was extracted with 3×5 mL of ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 58 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 4tt as a yellow solid: LC-MSD, m/z for C24H18BrFN2O2, [M+H]=465.4, 466.5, 467.4, 468.4; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.8 min; 1H NMR (400 MHz, CDCl3): δ 8.27 (1H, s), 8.12 (1H, m), 7.64 (1H, s), 7.56 (1H, m), 7.51 (1H, m), 7.47 (1H, m), 7.40-7.34 (2H, m), 7.19 (1H, m), 7.00 (1H, m), 5.46 (2H, s), 2.32 (3H, s), 2.31 (3H, s).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([OH:7])[CH3:6])#[N:2].[Cl:21]Cl>C(O)(=O)C>[C:1]([CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([OH:7])[CH3:6])#[N:2]
Reactant: ClCl
Reactant: CC(O)(CCC#N)c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(O)(CCC#N)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
2.76 g. of 1-cyano-3-(4-phenoxy-phenyl)-butan-3-ol are dissolved in 20 ml. of acetic acid, a solution of 0.8 g. of chlorine in 20 ml. of acetic acid is added dropwise at 20° while stirring, the mixture is stirred for a further one hour and evaporated and the residue is worked up in the customary manner to give 1-cyano-3-(4-p-chlorophenoxy-phenyl)-butan-3-ol, m.p. 68° - 70°.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:12]1([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:3]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2-c1ccccc1

Procedure:
Following the general procedure for the Suzuki coupling, 5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (27 mg, 0.080 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (26.5 mg, 0.080 mmol), Na2CO3 (22 mg, 0.21 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) in DMF (2.5 mL)/water (0.5 mL). The crude material was purified by chromatography on an SCX column (1 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-12) 1% MeOH in CH2Cl2 (13-33)→2% MeOH in CH2Cl2 (34-40)], yielding the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=5.31 (brs, 2H), 7.38-7.42 (m, 1H), 7.43 (s, 1H), 7.47-7.52 (m, 1H), 7.53-7.59 (m, 4H), 7.75 (dd, J=2.0, 8.4 Hz, 1H), 7.75-7.79 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.18-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.35-8.37 (m, 1H), 8.44 (s, 1H). MS (ES+): m/z 414.0 (25) [MH+]. HPLC: tR=3.4 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([C@@H:19]([CH3:22])[CH:20]=[O:21])[C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.Br[CH2:26][C:27]([CH3:29])=[CH2:28]>>[OH:21][CH:20]([CH2:28][C:27]([CH3:29])=[CH2:26])[CH:19]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:22]
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)C=O)cc1
Reactant: C=C(C)CBr
Product: C=C(C)CC(O)C(C)N(Cc1ccc(OC)cc1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared in analogy to the procedure described for step 23.7 from (S)-benzyl 4-methoxybenzyl(1-oxopropan-2-yl)carbamate and 3-bromo-2-methylprop-1-ene to afford the title compound as a 3:1 mixture of (2S,3R)- and (2S,3S)-diastereomer: tR=1.322 min (major isomer) and 1.329 min (minor isomer) (UPLC 1); tR=1.23 min (major isomer) and 1.24 min (minor isomer) (LC-MS 3); ESI-MS: 384 [M+H]+ (LC-MS 3).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[NH:14]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])=[CH:19][CH:20]=1)[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(O)C(=O)Nc1ccc(Nc2ccccc2)cc1
Yield: 772.4 %

Procedure:
A 500 milliliter resin pot was charged with 52 grams (0.05 moles) of α-hydroxy isobutyric acid from Example 1, 77.3 grams (0.42 moles) p-aminodiphenylamine, 1 gram p-toluene sulfonic acid and 140 mls. of xylene under a nitrogen blanket. A Dean-Stark water separator and a condenser was attached to the resin pot and the mixture was heated to vigorous reflux with H2O being removed as it was formed. After 3 hours of reflux the heat was removed and the product was allowed to crystallize in the resin pot under nitrogen. The product was broken up, washed with toluene, filtered and dried to obtain 104.4 grams (92% yield) of N-(4-anilinophenyl)-2-hydroxyisobutyramide with a melting point of 171°-174° C.