Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[NH:25]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCOC(C)=O>[CH:20]1([NH:23][C:24]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:11]=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[O:41])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: Clc1ccc(-c2nccc(N3CCOCC3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nccc(N3CCOCC3)n2)cc1)NC1CC1
Temperature: 140 °C
Yield: 46 %

Procedure:
4-(2-(4-chlorophenyl)pyrimidin-4-yl)morpholine (100 mg 0.5 mmol), (4-(3-cyclopropylureido)phenyl)boronic acid pinacol ester (181 mg, 0.6 mmol), Cs2CO3 (326 mg, 1.0 mmol) and Pd(PPh3)2Cl2 (18 mg, 0.025 mmol) were combined in dioxane (3 ml) and water 0.7 ml). The reaction mixture was then heated by microwave at 140° C. for 20 min. The reaction mixture was portioned between EtOAc and water. The organic layer was passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The solid residue was triturated with EtOAc, collected by filtration and dried in vacuo to afford the title compound (78 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].ClOC(C)(C)C.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>O1CCOCC1>[CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[N:5]2[CH2:28][CH:27]=[CH:26][CH:25]([C:24]([O:30][CH3:31])=[O:29])[N:4]2[C:3]1=[O:8]
Reactant: C=CC=CC(=O)OC
Reactant: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Agent: CC(C)(C)OCl
Solvent: C1COCCO1
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOC3CCCCO3)C(=O)N12
Temperature: 25 °C
Yield: 29.5 %

Procedure:
(B)(a) 1.21 g (5 mmol) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione were suspended in 20 ml of dry dioxan and the suspension was stirred at room temperature under a stream of nitrogen. A solution of 0.543 g (5 mmol) of tert.butyl hypochlorite in 5 ml of dry dioxan was added over a period of 15 minutes. The resulting blue solution was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in 10 ml of dry dioxan and the solution was added portionwise to a stirred solution of 0.616 g (5.5 mmol) of methyl penta-2,4-dienoate in 20 ml of dry dioxan. The blue color was allowed to fade between additions. When the addition was complete and no blue color persisted, the solution was stirred at room temperature for 1 hour. The resulting solution was evaporated in vacuo and the residue was chromatographed on silica gel. Elution with diethyl ether gave 0.52 g (29%) of methyl 2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 127.5°-128.5° C. (from diethyl ether).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C(C)=O)c1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
1-[2-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone (2.52 g) was suspended in a mixed solution composed of methanesulfonic acid (3 ml) and trifluoroacetic acid (50 ml), and the suspension was stirred at 70° C. for 30 min. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate powder and was then extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (1.23 g, yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.[CH2:21]([O:23][C:24](=[O:43])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([NH2:38])=[CH:36][C:35]([C:39]([CH3:42])([CH3:41])[CH3:40])=[N:34]2)[CH:28]=1)[CH3:22].O>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:43])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([NH:38][C:14]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:36][C:35]([C:39]([CH3:42])([CH3:41])[CH3:40])=[N:34]2)[CH:28]=1)[CH3:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A solution of 4-fluoro-phenylamine (111 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then added to a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT overnight then added to water (50 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (150 mg, 33%). 1H-NMR (CDCl3): 7.91 (s, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.37–7.34 (m, 2H), 7.28 (s, 1H), 7.17–7.16 (m, 2H), 6.98 (t, J=8.8 Hz, 2H), 6.59 (s, 1H), 4.04 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.77 (t, J=7.2 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 453 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26]1([CH2:32]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: ClCC1CCCCC1
Product: COc1ccc(-c2nn(CC3CCCCC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 45 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclohexylmethyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 45.0%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([NH:10][C:11]([NH:13][C:14]2[N:19]=[C:18](C)[CH:17]=[C:16](C)[N:15]=2)=[S:12])(=[O:9])=[O:8])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([CH3:27])=[N:3]1.BrN1[C:33](=[O:34])CCC1=O.[CH3:36][OH:37]>>[CH3:33][O:34][C:16]1[CH:17]=[C:18]([O:37][CH3:36])[N:19]2[S:12][C:11](=[N:10][S:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[C:5]=3[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:9])=[O:8])[N:13]=[C:14]2[N:15]=1
Reactant: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)NC(=S)Nc1nc(C)cc(C)n1
Reactant: O=C1CCC(=O)N1Br
Reactant: CO
Product: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)N=c1nc2nc(OC)cc(OC)n2s1

Procedure:
0.5 g of N-(1,3-dimethyl-4-ethoxycarbonyl-5-pyrazolesulfonyl)-N'-(4,6-dimethyl-2-pyrimidinyl)thiourea is suspended in 20 ml of methanol, followed by adding 0.2 g of N-bromosuccinimide while stirring at --4° C. to -5° C. The reaction mixture is stirred at the same temperature for 25 minutes. The separating crystals are filtered, and washed with methanol. Recrystallization of the crystals from acetonitrile yields 0.4 g of the title compound as colorless
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33]>N1CCCC1.C(O)C>[CH3:37][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8][O:7][C:6]3[CH:20]=[CH:21][CH:22]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[NH:14][C:13]2=[O:19])[NH:31][C:32]=1[CH3:33]
Reactant: CC(C)c1cccc(OCCc2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4cccc(C(C)C)c4)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 86.7 %

Procedure:
A mixture of 4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (28 mg, 0.095 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (20 mg, 0.095 mmol) and 1 drop of pyrrolidine in 1.0 mL of ethanol was heated at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 40 mg (87%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17]B(O)O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:10]1(/[CH:16]=[CH:17]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)C=CC1CCCCC1
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(/C=C/C2CCCCC2)cn1
Temperature: 90 °C
Yield: 75.9 %

Procedure:
Combine a mixture of 5-bromo-2-cyano-pyridine (2 g, 10.93 mmol), 2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (446 mg, 0.546 mmol) and 2M aqueous Na2CO3 (18.2 mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and heat at 90° C. overnight. Cool the reaction to room temperature and partition between EtOAc and water. Separate the aqueous phase and extract with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate (1.76 g, 76%). MS (APCI+) m/z: 213 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C(O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:27][CH:26]=1
Reactant: CC(=O)C(Cl)=NNc1cccc([N+](=O)[O-])c1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1cccc([N+](=O)[O-])c1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(3-nitrophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(3-nitrophenyl)hydrazono]-2-propanone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:23][CH:24]([CH3:43])[C:25]([NH:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[C:30]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:29]=1[F:42])=[O:26]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]([F:42])=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH3:43])[C:33]([F:34])=[CH:32][C:31]=3[F:35])[CH2:37][CH2:38]2)=[O:22])=[CH:9][CH:10]=1
Reactant: O=C(NCCCBr)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCNCC2)c1F
Product: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1F

Procedure:
Example 173 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl)acetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 588.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Cl:9].N#N.[CH3:12][CH2:13][OH:14].[Li][CH:16](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:12][C@H:13]([OH:14])[CH3:16]
Reactant: CCO
Reactant: Fc1ccc(Cl)c(Br)c1
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1cc(F)ccc1Cl
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A solution of 2-bromo-1-chloro-4-fluorobenzene (4.19 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give (2R)-1-(2-chloro-5-fluorophenyl)propan-2-ol (2.80 g, 74%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 1H), 7.02 (m, 1H), 6.90 (m, 1H), 4.14 (m, 1H), 2.82-2.96 (m, 2H), 1.46 (d, J=4.32 Hz, 1H), 1.28 (d, J=6.21 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+](C1C=[CH:23][C:19]([C:20](O)=O)=[C:18](N)C=1)([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45]N1C(=O)CCC1=O.CCOC(/N=N/C(OCC)=O)=O.C(N)(C)(C)C>O1CCCC1>[N+:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]([NH2:5])=[O:45])=[C:2]([NH2:1])[C:9]=1[C:19]([CH3:23])([CH3:20])[CH3:18])([O-:12])=[O:11]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C1CCC(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)(C)N
Product: CC(C)(C)c1c([N+](=O)[O-])ccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation of starting material: 2-amino-4-nitrobenzonitrile; Dissolve 4-nitro-2-aminobenzoic acid (500 mg, 2.75 mmol) in tetrahydrofuran (10 mL). Add triphenylphosphine (730 mg, 2.75 mL) and N-hydroxysuccinimide (316 mg, 2.75 mmol). Add a solution of diethylazodicarboxylate (0,433 mL,2.75 mmol) and stir at room temperature under nitrogen for 10 minutes. Add tert-butylamine (1.1 mL, 5.5 mmol) in tetrahydrofuran (5 mL) directly to the reaction to yield after workup the 4-nitro-2-amino-tert-butylbenzamide.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]3[C:14](OC)=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH2:23])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([NH2:23])[N:10]=[CH:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[N:15][C:14]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cnc(N)nc2NC2CCCC2)c(OC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2c3cnc(N)nc3n(C3CCCC3)c2n1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
A 10 mL reaction vessel was charged with N4-cyclopentyl-5-(2,6-dimethoxypyridin-3-yl)pyrimidine-2,4-diamine (267) (50.0 mg, 159 μmol) dissolved in dry pyridine (1 mL) under argon. Sodium bis(trimethylsilyl)amide in THF (1.0M, 0.349 mL, 349 μmol) was added and the reaction heated with microwave energy (300 W) for 12 minutes at 150° C. The solvent was removed in vacuo. Silica gel chromatography of the residue (gradient elution dichloromethane/0-5% methanol) afforded compound 268 as an off-white solid (28 mg, 62%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:17][CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Br)c(OC(C)C)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 0.50 g (1.7 mmole) of ethyl 5-bromo-4-hydroxy-3-methyl-1-benzofuran-2-carboxylate (Example 119, Step 1) in 7 mL DMF was added 0.51 g (3.75 mmole) of potassium carbonate and 0.48 mL (3 mmole) of 2-bromopropane and the reaction was stirred at room temperature overnight. The solvent was concentrated in vacuo, and the residue was extracted with ethyl acetate and water. The organic layer washed with water and brine, dried over sodium sulfate, filtered, and concentrated to provide 0.58 g of ethyl 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylate. Yield: 100%; m.p. 48-50° C.; MS: 341.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([Br:26])[CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[Br:26][C:15]1[CH:14]=[C:13]([C:6]2[CH:5]=[C:4]([OH:3])[N:30]=[N:31][C:7]=2[CH2:8][CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)c(Br)c1)C(O)C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nnc(O)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3-bromo-4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (4.39 mmol, 2.0 g) and hydrazine hydrate (2.0 mL) in acetic acid (10 mL) was kept stirring at 120° C. for 3 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water, extracted with ethyl acetate dried and concentrated under reduced pressure, dried to provide 5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-ol (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][C:26]=3[F:28])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)cc1F
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2F)C1
Yield: 86.8 %

Procedure:
The title compound (D108) (84 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 2,4-Difluorophenol (0.027 ml, 0.284 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC(OC)=CC=1OC)[CH2:8]2)=[O:4].[C:25]1(OC)C=CC=CC=1.O.C(Cl)Cl.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8]2)=[O:4])[CH3:25]
Reactant: COc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1OC)C2
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CNC2

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (215 mg) and anisole (200 μl) in 1 ml of TFA was heated at 140° C. for 30 minutes in a CEM discover microwave synthesiser. The reaction was partititioned between water and DCM, the water layer was separated, washed with DCM then evaporated and re-evaporated with toluene/MeOH (×2) to give 105 mg of the title compound. 1H NMR (DMSO-d6) 9.70 (2H, br s), 8.02 (1H, s), 8.98 (1H, d), 7.57 (1H, d), 4.60 (2H, s), 4.56 (2H, s), 3.89 (3H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH:8]=[C:7]3[O:13][CH2:14][O:15][C:6]3=[CH:5][C:4]=2[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN1C(=O)CCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[CH:8]=[C:7]4[O:13][CH2:14][O:15][C:6]4=[CH:5][C:4]=3[N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)nc2cc3c(cc12)OCO3
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c3cc4c(cc3n2)OCO4)CC1
Yield: 39 %

Procedure:
A mixture of 6-chloro-[1,3]dioxolo[4,5-g]quinazolin-8-ylamine (0.9 g, 4.02 mmol equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.61 g, 8.05 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.6 g (39%) of the title compound. MS (ISP): 388.4 [M+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].O>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:3])[CH:11]=1
Reactant: BrBr
Reactant: COc1ccc(F)c(C=O)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Bromine (15 ml, 300 mmol) was added slowly to a solution of 2-Fluoro-5-methoxy-benzaldehyde (23.12 g, 150 mmol) in chloroform (500 ml), and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes) to give the product. Yield: 20.7 g, 60%. 1H NMR (CDCl3) δ: 3.93 (s, 3H), 7.08–7.13 (m, 1H), 7.29 (d, J=12.4 Hz, 1H).
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:4]>O1CCCC1>[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:1])(=[O:13])=[O:12])[CH3:4]
Reactant: N
Reactant: CC(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(Cl)c1ccccc1S(N)(=O)=O

Procedure:
A solution of ammonia (1.2 ml) in tetrahydrofuran (100 ml) at -70° was contacted rapidly with a solution of 2-(1-chloroethyl)benzenesulfonyl chloride (4.32 g, 18.1 mmol) in tetrahydrofuran (50 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and washed with a small volume of water and brine. The dried (MgSO4) solution was evaporated to give 4.7 g of off white solid which was recrystallized from chloroform to give 3.13 g, m.p. 121°-122°.