Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1.CCO>C1COCC1>[OH:35][CH:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:29](=[O:33])[O:30][CH2:31][C:32]=2[C:24]=1[CH3:23])[CH2:36][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[C:3]=2[CH3:2])[O:21][CH3:22])[CH2:16][CH2:17]1
Reactant: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COC(CN1CCN(CC(O)c2ccc3c(c2C)COC3=O)CC1)c1ccc2c(c1C)COC2=O
Temperature: 120 °C

Procedure:
4-Methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride (40 mg, 0.14 mmol), 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (79 mg, 0.41 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2 mL) and THF (0.5 Ml). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 120° C. for 1 hour; LC indicated completion of the reaction. The solution was concentrated to dryness, dissolved in MeOH (3.5 Ml), filtered and was then purified by mass-directed HPLC to give 5-[2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-(methyloxy)ethyl]-4-methyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O-:29])=O)=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].Cl.[NH2:40][OH:41]>CO.C[O-].[Na+]>[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:40][OH:41])=[O:29])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1
Reactant: NO
Reactant: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)[O-])c1ccc(C2=CCOc3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
(5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction (34e) (0.10 g, 0.23 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 32%) as a white solid. MS found: (M−H)+=433.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:26]([NH:30][C:21]1[CH:20]=[C:19]([C:18]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:24]=[CH:23][N:22]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1cccc2c(-c3ccnc(F)c3)c(-c3ccc(F)cc3)nn12
Reactant: CCCCN
Solvent: CCOC(C)=O
Product: CCCCNc1cc(-c2c(-c3ccc(F)cc3)nn3c(OC)cccc23)ccn1
Temperature: 130 °C

Procedure:
In a sealed-tube was combined 2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-α]pyridine (from Example 30, 20 mg, 0.06 mmol) and n-butylamine (2.0 mL, 1.5 g, 20 mmol), and the reaction was placed in a pre-heated oil bath at 130° C. The reaction was stirred at 130° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube was transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 2.0 mg (0.005 mmol, 8%). 1H NMR (d6-acetone): δ 8.04(d, 1H, J=5.1 Hz), 7.74(dd, 2H, J=5.7, 9.0 Hz), 7.33–7.38(m, 2H), 7.22(t, 2H, J=9.0 Hz), 6.45–6.54(m, 3H), 4.25(s, 3H), 3.30–3.40(m, 2H), 1.60(quint, 2H, J=7.2 Hz), 1.45(sext, 2H, J=7.2 Hz), 0.9(t, 3H, J=7.2 Hz). MS (ES+ve): 391.1 (100, M+), 376.3 (100).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N12CCCN=C1CCCCC2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:27])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
Process B: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (561 mg) was dissolved in toluene (20 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) was added and perfluoro-1-octanesulfonylfluoride (0.93 mL) was then added dropwise while the mixture was chilled in an ice water bath. After stirred at 2° C. for 1 hour, the reaction mixture was poured on a silica gel pad and was eluted with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow oil (447 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1>O1CCOCC1.C1COCC1>[CH2:15]([N:7]1[C:6]2[CH:17]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=2[CH2:11][N:10]([CH2:13][CH3:14])[CH2:9][CH2:8]1)[CH3:16]
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCN1CCN(CC)c2cc(N)ccc2C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5one (22.0 g, 0.0944 mol) in dioxane (400 mL) was added borane dimethyl sulfide complex solution (2 M in THF, 118 mL, 0.236 mol) and heated at 75° C. for 4 hr. The reaction was quenched with ethanol (100 mL) and stirred at room temperature for 18 hr., then evaporated. To the residue was added hydrazine hydrate (100 mL) and heated at 95° C. for 4 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) were added, distilled and the reaction evaporated. The residue was extracted with DCM, evaporated, dissolved in ether, filtered and evaporated to give 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an oil (16.0 g, 84%). LCMS (m/e) 220 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.79-6.71 (d, 1H, J=7.83 Hz), 6.49 (br, 1H), 6.01-5.99 (d, 1H, J=7.83 Hz), 4.79 (s, 2H), 3.07-3.02 (q, 2H, J=6.82 Hz), 2.85-2.83 (t, 2H, J=8.08 Hz), 2.70-2.68 (t, 2H, J=8.09 Hz), 1.13-1.10 (t, 3H, J=7.07 Hz), 1.00-0.97 (t, 3H, J=7.32 Hz), 712d) 5-Chloro-N*2*-(1,4-diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidin-2,4-diamine was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.068 g, 0.00023 mol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (0.081 g, 0.00023 mol), camphorsulfonic acid (0.0187 g, 0.0008 mol) and methoxyethanol (10 mL). The mixture was heated at 95° C. for 18 hr. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with THF/methanol (10-1) giving the product as a tan solid (0.053 g, 43%). Mp 165-166° C. LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 9.07 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.65 (d, 1H), 7.15-7.13 (d, 1H, J=8.33 Hz), 7.01 (s, 1H), 6.84-6.82 (d, 1H, J=8.08 Hz), 6.69 (s, 1H), 6.49-6.47 (d, 1H, J=8.59 Hz), 3.80 (s, 3H), 3.76 (t, 2H, J=4.05), 3.54 (s, 2H), 3.14 (t, 3H), 3.01-2.99 (q, 2H, J=7.07 Hz), 2.90-2.84 (m, 2H), 2.78-2.69 (m, 2H), 2.40-2.30 (m, 2H), 1.11-1.08 (t, 3H, J=6.57 Hz), 1.03-1.00 (t, 3H, J=7.33).
Reaction SMILES: C(N[NH:9][CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:12]([N:9]([CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:34](=[O:35])[CH2:33][Cl:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CNNCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(O)CN(Cc1ccccc1)C(=O)CCl
Temperature: -50 °C
Yield: 93 %

Procedure:
To a solution of N-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (3.5 g) in CH2Cl2 (60 ml), NaOH (0.6 g) and water (16 ml) were added at 0° C. The whole was cooled to -50° C. and chloroacetyl chloride (1.1 ml) diluted in CH2Cl2 (10 ml) was added dropwise. The organic extracts were combined and washed with a saturated solution of NaCl, drying was carried out over Na2SO4 and the solution was then evaporated to dryness, so obtaining N-benzyl-N-chloroacetyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenylpropylamine (4.0 g; yield 93%) as an oil, chromatographically pure, which is used as such.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:20])([F:19])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1.[Br:24]Br>ClCCl.CCCCCC>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([Br:24])=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:19])([F:20])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(N)c1SC(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: N#Cc1c(SC(F)(F)F)c(N)n(-c2ccc(C(F)(F)F)cc2)c1Br
Yield: 52 %

Procedure:
To a suspension of 1.17 g (3.30 mmoles) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.46 ml (0.34 g, 3.3 mmoles) of triethylamine in 20 ml of chloroform cooled to -20° C. was added a solution of 0.19 ml (0.59 g, 3.7 mmoles) of bromine in 5 ml of chloroform. The reaction mixture was stirred at -20° C. for 1 hour and then allowed to warm to 0° C. Another 0.04 ml (0.13 g, 0.8 mmole) of bromine was then added and after 15 minutes of additional stirring, the reaction mixture was diluted with dichloromethane and partitioned with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 1.11 g of a brown solid. This material was combined with that from a previous reaction of 1.00 g (2.8 mmoles) of 1-(4-trifluoromethylphenyl)- 2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.15 ml of bromine. Chromatography on silica gel eluting with 3:1 v/v dichloromethane-hexane furnished 1.40 g (52%) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyano-5-bromopyrrole (EXAMPLE 14A) as a yellow solid. Recrystallization from hexane-ethyl acetate provided the product as light yellow platelets, melting point about 175° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl.CO>[OH-].[Na+].C(O)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 72.9 %

Procedure:
The solution of 4-[(2-ethoxycarbonylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) in a mixture of 1N aqueous sodium hydroxide solution (0.43 ml) and ethanol (4.0 ml) was stirred at ambient temperature for 5.5 hours. The resulting solution was neutralized with 1N hydrochloric acid and methanol was removed in vacuo. The residue was diluted with water and the aqueous layer was extracted with chloroform. Drying, filtering and removal of solvents afforded 4-[(2-carboxyindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg) as a yellow amorphous.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1F
Temperature: 90 °C

Procedure:
To a solution of 2.5 g (27.0 mmol) of 2-fluoro-4-iodobenzoic acid (Compound B) in 11 mL (8.6 g, 187.5 mmol) of ethanol was added 0.3 mL of c. sulfuric acid. The reaction mixture was heated to reflux in an oil bath (90° C.) for 1.75 hours, fitted with a short path distillation apparatus, distilled and then allowed to cool to ambient temperature. The reaction mixture was extracted and partitioned between pentane and water and the layers were separated. The aqueous phase was washed with pentane and the organic phases were combined. The combined organic phase was washed sequentially with sat. NaHCO3 (aq.) solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C(=O)Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Solvent: CCC(C)O
Product: CC(C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12)c1ccccc1
Yield: 55.8 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-propanamide (170 mg, 0.469 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (282 mg, 1.41 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20->0/100, 30 CV) to yield tert-butyl (3R)-1-(5-bromo-3-(2-phenylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (142 mg, 55.8% yield) as a solid.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: Nc1ccccc1
Product: CC(C)(CC(O)(C=Nc1ccccc1)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 1, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 64 μl of aniline are converted into 180 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1>O1CCOCC1.C(OCC)(=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)[CH:27]=1)#[N:29]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)c1
Temperature: 125 °C
Yield: 54.8 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.36 g) and 2-chloro-4-cyanopyridine (0.14 g) in dioxane (1 mL) was heated at 125° C. in a sealed tube for 5 days. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride to 2% ethanol/methylene chloride gradient gave the above-named compound (0.22 g) mp 152-153° C. NMR (CDCl3) 8.45 (1H, m), 7.86 (3H, m), 7.48 (2H, d), 7.20 (1H, br s), 7.07 (1H, s), 6.91 (1H, m).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[OH-].[NH4+:14]>CO.[Ni]>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([NH2:14])[CH3:2])=[CH:5][C:6]=2[CH2:10][CH2:9]1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc2c(c1)CCO2
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)CCO2
Yield: 70 %

Procedure:
A mixture of 5-acetyl-2,3-dihydrobenzo[b]furan, oxime, (Preparation 3, 2.7 g, 16 mmole) in methanol (50 mL), ammonium hydroxide (5 mL) and Raney nickel (3 mL) was hydrogenated on a Parr hydrogenator (H2, 50 psi) for 2 days. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using methanol (100%) to give the title compound (1.74 g, 70%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[CH3:11]
Reactant: Cc1ccnc(F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(F)c1N

Procedure:
To a solution of 10.1 g (grams) (65 mmol (millimole)) of 2-fluoro-4-methyl-3-nitropyridine in 200 mL (milliliter) of ethyl acetate was added 25 g (0.40 mol) of acetic acid and 0.8 g of 5 percent palladium on carbon catalyst. This mixture was shaken under 50 psig (pounds per square inch gauge, 2400 kiloPascals) pressure of hydrogen for 18 hours, was filtered, and was concentrated by evaporation under reduced pressure to obtain an oil. This oil was partitioned between dilute aqueous sodium bicarbonate and ether. The organic phase was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography to obtain 7.2 g (88 percent of theory) of the title compound as a colorless solid melting at 63°-64° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29]>C1COCC1>[CH3:18][C:9]([NH:8][CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29])([CH3:19])[CH2:10][C:11](=[O:12])[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(N)CC(=O)N1CCCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(CC(=O)N1CCCC1)NCC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of 3-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one trifluoroacetic acid (0.28 g, 1 mmol) in anhydrous THF (5 mL) was added potassium carbonate (0.55 g, 4 mmol). After stirred at room temperature for 1 h, the mixture was filtered through a Celite pad, and rinsed with ethyl acetate (5 mL). To the above filtrate was added (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.12 g, 0.5 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 12 h. Most of solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and H2O (5 mL). The aqueous layer was further extracted with CH2Cl2 (10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by chromatography (silica gel, 4 to 10% CH3OH/CH2Cl2 gradient) to give compound 1 (0.12 g, 74% overall yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC(C)(C)C)cn1
Yield: 20 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted using tert-butylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 24 mg, 20%) which was obtained as a colorless gum. MS: m/e=367.2 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:32])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>CN(C=O)C>[CH2:33]([NH:35][C:36](=[O:37])[N:25]([C@H:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:13](=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[C@@H:16]([CH3:32])[CH2:17]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:34]
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccccc3)C[C@@H]2C)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCNC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Temperature: 90 °C

Procedure:
(±)-Cis-3-ethyl-1-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-1-phenyl-urea was synthesized using general procedure A, substituting ethyl isocyanate for acetyl chloride using the following procedure. To a solution of (±)-cis-(3-methoxy-phenyl)-(2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl)-methanone in DMF was added ethyl isocyanate and reaction mixture was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated. Crude mixture was purified by flash chromatography on silica gel using gradient elution hexane-ethyl acetate (5-20%).