Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[CH3:15]
Reactant: CNC
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Solvent: CCO
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Temperature: 130 °C

Procedure:
Alternatively, 6-chloro-pyrido[3,4-d]pyrimidin-4-one (26.14 g) was treated with 2N dimethylamine in ethanol (200 ml) and heated at 130° C. in a Parr bomb for 3 days. The cooled mixture was filtered and triturated from isopropanol to give the title compound (16.61 g) as a yellow solid; m/z (M+1+)191.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC>C1COCC1.CCOCC.Cl>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([Si:12]([CH3:15])([CH3:14])[CH3:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc2sccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2c(Br)cccc2s1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of ˜80% pure 4-bromobenzothiophene (580 mg, 2.7 mmol) and chlorotrimethylsilane (0.70 mL, 5.4 mmol) in dry THF (10 mL) was cooled to −70° C. and 2 M LDA in 1:1 THF/heptane (1.35 mL, 5.4 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1.5 h and diluted with ether (80 mL) and 5% aq HCl (20 mL). The organic layer was separated, washed with sat'd aq NaHCO3 (20 mL) and dried over MgSO4. Removal of the solvent left 4-bromo-2-(trimethylsilyl)benzothiophene (740 mg, 95%) as an amber oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])CCC.[NH2:18][C:19]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][C:20]=1[C:21](N(OC)C)=[O:22]>C1COCC1>[NH2:18][C:19]1[C:20]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][C:9]([F:12])([F:11])[F:10])=[O:22])=[CH:27][C:28]([Br:31])=[CH:29][N:30]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[C:23]([CH2:26][C:27](=O)[CH3:28])(=O)[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]2[C:2]3=[N:1][C:23]([CH3:24])=[CH:26][C:27]([CH3:28])=[C:3]3[C:4]([C:21]#[N:22])=[CH:5]2)=[CH:19][CH:18]=1
Reactant: N#Cc1cc(N)n(C(c2ccccc2)c2ccc(F)cc2)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C(c3ccccc3)c3ccc(F)cc3)c2n1

Procedure:
To a solution of 5-amino-1-[(4-fluorophenyl)(phenyl)methyl]-1H-pyrrole-3-carbonitrile (13.7 g, 47.0 mmol) in ethanol (200 ml) was sequentially added acetylacetone (5.66 g, 56.6 mmol) and concentrated hydrochloric acid (2.0 ml). The mixture was heated under reflux for 3 hours, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#N)[C:9](=[O:15])[C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].[NH:25]1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]3=[N:18][C:17]([NH2:25])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[C:10]3[C:9](=[O:15])[C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2occ(C#N)c(=O)c2c1
Reactant: CCOC(=O)CC#N
Reactant: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(=O)c3cc(C(C)=O)ccc3oc2nc1N
Temperature: 25 °C

Procedure:
In ethanol (800 ml) was suspended 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile (32 g). To the suspension were added ethyl cyanoacetate (23.9 ml) and piperidine (23.7 ml). The mixture was refluxed for one hour, then cooled to room temperature. The resulting crystals were collected by filtration, washed with ethanol, then with acetone, followed by drying to give ethyl 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate as yellow crystals (46.3 g). Melting point: >300° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9]O>CC(O)=O>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 3-Bromo-2-methyl-pyridine (1.96 g, 11.4 mmol) in glacial HOAc (20 mL) at room temperature was added 50% H2O2 (0.77 mL) and the solution was heated to 70° C. After 2 h, the reaction mixture was cooled to room temperature, additional H2O2 (0.80 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and treated with saturated aqueous NaHCO3 (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 3-Bromo-2-methyl-pyridine 1-oxide (1.79 g, 84%) as a white solid. 1H NMR (CDCl3) δ 2.70 (s, 3H), 7.00 (t, 1H, J=7.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=6.5 Hz). 3-Bromo-2-methyl-pyridine 1-oxide was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
4-Chloro-3-nitro-benzenesulphonyl chloride (2.56 g, 10 mmol) was added in small portions to a solution of N-methyl piperazine (1.33 ml, 12 mmol) in DCM (25 ml) at 0° C. To this solution was added triethylamine (2.08 ml, 15 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 2 h and then reduced in vacuo. The residue was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried (MgSO4) and reduced in vacuo. Purification with column chromatography eluting with 0-20% methanol in ethyl acetate gave 1-(4-chloro-3-nitro-benzenesulphonyl)-4-methyl-piperazine as an off-white solid (1.84 g, 58%). (LC/MS: Rt 1.84, [M+H]+ 319.97).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][NH:16][C:3]1=[O:4]
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CC(c2ccccc2)=NNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A 250 mL three-neck round bottom flask fit with a temperature probe and condenser is charged with 7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid 1 and 20 ml of ethanol (95%). The suspension is cooled to below 10° C. and 2.2 ml (42 mmole, 1.05 equiv.) of hydrazine monohydrate in 10 mL of ethanol is added dropwise at a rate that maintains the solution temperature at below 20° C. Upon addition, the suspension changes to a pale yellow solution. After addition, the reaction mixture is heated to reflux and stirred for 2 h, and after 20 minutes of heating, a solid is seen in the mixture. Once the reaction is completed, the flask is removed from the oil bath and cooled to ambient temperature. Upon cooling, white crystals form in the flask, which are collected by filtration. The solid is washed first with 30 mL of, 2N NaHCO3, followed by 60 mL Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give the desired product 2 in 96.1% yield. [See Hansen, K B et al. Organic process research & development, 2005, 9, 634-639; Nelson, D A. US 20050137397A1. Coudert, P at al. Journal of Heterocyclic Chemistry, 1988, 25(3), 799-802.]
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.ClCCl.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.8 %

Procedure:
6-Nitro-1-indanone (10.0 g, 56.4 mmol) was dissolved in methanol (200 mL), a 10% palladium-carbon powder (500 mg) was added, and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere. To the reaction solution were added dichloromethane and ethyl acetate to dissolve the precipitated crystals, and the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was washed with methanol to give the title compound (6.71 g, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:39])[N:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.CC[N:42](C(C)C)C(C)C.CS([Cl:53])(=O)=O>C1COCC1>[ClH:53].[ClH:53].[NH2:42][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:24][C:25]([C:27]3[C:28](=[O:39])[N:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:3][C:2]=2[F:1])=[CH:20][CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(Oc2ccncc2-c2ccc(CCO)cc2)c(F)c1)c1cccn(-c2ccccc2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cl
Product: NCCc1ccc(-c2cnccc2Oc2ccc(NC(=O)c3cccn(-c4ccccc4)c3=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To N-(3-fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (Compound C of Example 67, 40 mg, 0.077 mmol) in THF (1 mL) was added DIPEA (27 uL, 0.154 mmol) followed by methanesulfonyl chloride (Aldrich, 7 uL, 0.092 mmol). After stirring at rt for 30 min, the reaction was concentrated in vacuo. The residue was dissolved in 3 mL of ethanol and transferred to a pressure tube. Ammonium hydroxide (7 mL) was added and the tube was sealed and heated at 50° C. for 8 h. After cooling to rt, the reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL) then brine (1×10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by prep HPLC. The appropriate fractions were concentrated to remove methanol and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (2×20 mL) and the pooled organic extracts were washed with brine (1×10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dissolved in dioxane (2 mL) and charged with 1N HCl in ether (1 mL). The solution was concentrated and the resulting solid was lyophilized from acetonitrile/water to give the HCl salt of the title compound (24 mg, 53%) as a white solid. 1H NMR (DMSO-d6) δ 12.13 (s, 1H), 8.74 (s, 1H), 8.55-8.51 (m, 2H), 8.09 (dd, 1H, J=6.4, 2 Hz), 8.03 (m, 1H), 7.64 (d, 2H, J=6 Hz), 7.63 (m, 1H), 7.54-7.41 (m, 6H), 7.38 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=6 Hz), 6.68 (t, 1H, J=6.8 Hz), 3.02 (m, 2H), 2.89 (m, 2H); MS(ESI+) m/z 521.27 (M+H)+.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.I[CH2:17][CH2:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.[I-].[K+]>CC(C)=O.CC(=O)CC>[N:28]1([CH2:17][CH2:18][CH2:19][CH2:20][O:15][C:6]2[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]3[O:3][CH:2]=[CH:1][C:5]=23)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Reactant: c1cn[nH]c1
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: O=c1ccc2c(OCCCCn3cccn3)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
500 mg (2.473 mmol) of 5-hydroxypsoralen and 893 mg (4.088 mmol) of 4-iodo-1-chlorobutane were stirred at 25° C. in 30 ml of anhydrous acetone in the presence of an excess (2.0 g) of anhydrous potassium carbonate for 28 hours. The progress of the reaction was monitored by thin layer chromatography. After 28 hours the reaction mixture was concentrated under reduced pressure and distilled off the solvent almost completely. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and filtered. The solids were washed with water to neutral pH and dried. The dried solids were suspended in petroleum ether, filtered and dried under vacuum. To the solids were added 400 mg (5.875 mmol) of pyrazole, 2.0 g anhydrous potassium carbonate, catalytic amounts of potassium iodide, 30 ml of 2-butanone and the reaction mixture was refluxed for 50 hours. After 50 hours the reaction mixture was concentrated under vacuum. The residue was diluted with water and acidified to pH 1 with concentrated hydrochloric acid. The separated oily organic layer was extracted with 3×50 ml of dichloromethane. The dichloromethane layer was then washed with 0.75% aqueous sodium hydroxide to separate the un-reacted 5-hydroxypsoralen followed by washing with acidic water. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in an acetone-methanol mixture, treated with charcoal and re-crystallized from an ethyl acetate-petroleum ether (20:80) mixture.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.NN.C(OCC)C>C(O)C>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH2:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCC1(CCN)CCCCC1)(c1ccccc1)c1ccccc1
Yield: 104 %

Procedure:
To a solution of N-[2-[1-[2(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-ethyl]phthalimide (1.52 g) dissolved in ethanol (30 mL) was added hydrazine monohydrate. The reaction solution was heated under reflux for 4 hours. To this was added diethyl ether and the insolbles were filtered off. The solvent was then distilled off under reduced pressure. To this was added chloroform, and the solution was made basic by addition of a 1N aqueous hydroxide solution. The solution was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:13]([O:17][C:18](=[O:36])[C:19]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([Cl:34])[C:22](Cl)=[N:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>C(#N)C.CCOC(C)=O>[C:13]([O:17][C:18](=[O:36])[C:19]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([Cl:34])[C:22]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[N:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: CC(O)CN
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Temperature: 25 °C
Yield: 74.6 %

Procedure:
1-Amino-propan-2-ol (2.44 g, 30.3 mmol) and triethylamine (0.42 mL, 3.03 mmol) were added to a solution of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloro-nicotinic acid tert-butyl ester (1.37 g, 3.03 mmol) in acetonitrile (30 mL). The reaction was heated to reflux. After 23 hours the reaction was cooled to room temperature and diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried over Na2SO4 and concentrated to a white solid. Purification by flash column chromatography (20:1 dichloromethane/methanol) provided the desired product as a white solid (1.11 g, 75%). MS APCI (+) m/z 492, 494 (M+, Cl, Br pattern) detected.
Reaction SMILES: [NH2:1][C:2]1[C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]2)=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(CC#N)cnc23)CC1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCc1cnc2c(C(=O)Nc3cnccc3N3CCC(N)CC3)c(N)nn2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
To a solution of tert-butyl N-[1-[3-[[2-amino-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-4-pyridyl]-4-piperidyl]carbamate prepared according to a method similar to the one described in Example 1 (70 mg, 0.1424 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol) and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was evaporated to dryness and purified by HPLC: 10-90% ACN in Water (TFA modifier) and the fractions were freeze-dried. The solid residue was dissolved in methanol (1 mL) and loaded onto a pre-wetted (15 mL methanol) 2 g SCX-2 cartridge. The cartridge was washed with methanol (2×15 mL) then the product eluted as a free base using 2M ammonia in methanol solution (3×15 mL). The product-containing fractions were evaporated to dryness, re-dissolved in water/methanol and freeze-dried to afford the desired product as a yellow solid (17 mg, 31%). MS (ES+) 391.1.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:41])[S:27]([C:30]([CH3:31])([CH3:33])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)(C)C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide (100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) was added in a single portion. After 25 minutes, this mixture was cooled to 0° C. in an ice-water bath, and iodomethane (0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture was allowed to gradually warm to ambient temperature, gradually becoming a pale yellow suspension. After 2 h water (2 mL) was added very carefully. The resulting mixture was partitioned between ethyl acetate and saturated aq. NH4Cl solution. The aqueous phase was back-extracted (2×) and the combined organics were washed with sat. aq. NaCl solution (2×), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to an oily residue that was chromatographed on a 12 g silica column, eluting with a gradient of 0 to 35% EtOAc in hexanes. Fractions containing the sulfonamide product were pooled and concentrated to give the title compound. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>O>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([O:10][CH3:11])[CH:8]=1)[NH:1][C:14](=[O:15])[N:13]=[CH:4]2
Reactant: COc1cc(Br)cc(C=O)c1N
Reactant: NC(N)=O
Solvent: O
Product: COc1cc(Br)cc2cnc(=O)[nH]c12
Temperature: 180 °C
Reaction time: 1 h

Procedure:
2-amino-5-bromo-3-methoxybenzaldehyde (2.5 g, 10.87 mmol) is homogeneously mixed with urea and the mixture is heated to 180° C. The melt formed is kept at this temperature for 1 h. Then the reaction mixture is mixed with water, the precipitate formed is filtered off, dried and 6-bromo-8-methoxy-1H-quinazolin-2-one (HPLC-MS: tRet.=1.53 min MS(M+H)+=255/257; method FSUN) is obtained.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(OCc2ccc(CC(Cl)=NO)cc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(5-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Manufacturing Example 44-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol) at room temperature, which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (57.4 mg, 65.6%).