Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[O:13][CH:11]1[CH3:12]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC1CO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
General Procedure FF: To a THF (5 mL) solution of 1.0 M of 4-chlorophenylmagnesium bromide in Et2O (10.0 mL) was added a solution of propylene oxide (0.87 g, 15 mmol) in THF (5 mL) at −78° C. under nitrogen and stirred. The mixture was slowly warmed to rt. The mixture was quenched with sat. aq NH4Cl (10 mL) and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.23-1.26 (m, 3H), 1.44 (d, J=3.8 Hz, 1H), 2.65-2.80 (m, 2H), 3.97-4.07 (m, 1H), 7.14-7.18 (m, 2H), 7.28-7.32 (m, 2H).
Reaction SMILES: N.[OH:2]O.[C:4]([C:6]1[C:7]([CH3:36])=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:9]=[CH:10][CH:11]=1)#[N:5]>C(O)C>[C:4]([C:6]1[C:7]([CH3:36])=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:2])[NH2:5]
Reactant: Cc1c(C#N)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Reactant: OO
Agent: N
Solvent: CCO
Product: Cc1c(C(N)=O)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30% Aqueous NH3 solution (4.2 mL) and 35% aqueous H2O2 solution (1.4 ml) are added at 0° C. to a solution of 2-((3S)-6-((1R)-4-(3-cyano-2-methylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (30 mg) in ethanol (5 mL). The mixture is stirred at room temperature for 12 hours, while warming to room temperature. The mixture is concentrated, diluted with water and neutralized with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 29 mg; LC (method 20): tR=5.02 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[S:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[S:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CSc2ccc(CCl)cc21
Product: COCCCN1C(=O)CSc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.570 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.359 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]thiazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.14.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2ocnc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of benzo[d]oxazole-5-carboxylic acid (7.8 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (7.0 g, 1.5 eq), HOBt (7.76 g, 1.2 eq) and EDCI (11 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (19 g, 4.0 eq) dropwise at 0° C. The mixture was then stirred at rt overnight, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (6.0 g, 51%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.16 (1H), 7.80 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 3.56 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:18][NH2:19]>>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Reactant: CN
Product: CNC(=NCCSCc1cnccn1)NC#N

Procedure:
Reaction of this isothiourea with methylamine by the procedure of Example 3(c)(ii) gives the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.C(N(CC)CC)C.C[O-].[Na+]>CO>[N+:10]([C:6]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]([OH:2])=[C:8]([O:9][CH3:1])[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
0.1 mol (21.2 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to a solution of 0.12 mol (16.8 ml) of triethylamine, 0.4 mol of sodium methylate (72 g of a 30% strength solution in methanol) and 60 ml of methanol. The mixture is heated for 10 minutes at the refluxing temperature of the methanol. After the mixture has been cooled to 0° C., the phenate of the expected product is drained. The phenate is dissolved in 300 ml of water at 60° C. The solution is filtered on paper in order to remove a resin. On cooling and neutralization of the filtrate with acetic acid, the expected product precipitates. After being dried, the 4,5-dinitro-2-methoxyphenol thereby obtained is recrystallized from isopropanol. It melts at 172° C. (literature: 177° C.).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:23]=[C:22]([C:2]2[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:21]=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Nc1ccc(CC2CCCC2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
2-bromo-4-(cyclopentylmethyl)aniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-(cyclopentylmethyl)aniline.
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]([C:8]([F:11])([F:10])[F:9])([C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h

Procedure:
Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) is added dropwise at ambient temperature to a stirred mixture of sodium hydride (2.4 g. of a 60% dispersion in oil) and dimethylformamide (100 ml.). The mixture is stirred for 4 hours, 4-chlorobenzyl chloride (8.4 g.) is added, and the stirring is continued for 6 days. The mixture is filtered, and the filtrate is evaporated in vacuo. The residue is fractionally distilled at 0.1 mm. pressure, collecting the fraction, (9.9 g.) b.p. 78°-80° C., m.p. 32°-33° C, which is crystallized from pentane to give ethyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, m.p. 33° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][OH:19])[CH2:9][O:10][CH:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].C1(C=CC(O)=CC=1)O.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:12]([F:15])([F:14])[F:13])[C@H:16]1[CH2:17][O:19][NH:18]2
Reactant: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: Fc1ccccc1[C@]12CO[C@H](C(F)(F)F)[C@H]1CON2
Temperature: 128 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone oxime (1.085 kg, 3.328 mol) in xylenes (6.9 L) was added hydroquinone (86.2 g, 0.8 mol) at rt. The solution was heated to 128° C. (internal temperature) for 18 h. The solution was cooled to rt, and hexanes (7.0 L) was added, followed by 4.0 M aq. HCl (2.4 L). The reaction mixture was stirred for 1 h, and filtered. To the solid was added water (2.0 L), methyl tert-butyl ether (7.0 L) and 25% wt. aq. NaOH (0.4 L). The aq. layer was extracted once with methyl tert-butyl ether (7.0 L), the organics were combined, washed with 27% aq. NaCl (2.0 L) and concentrated under vacuum to a black oil (512.0 g, 56%). 1H NMR (500 MHz, CDCl3) δ ppm 7.64-7.52 (m, 1H), 7.39-7.31 (m, 1H), 7.19 (td, J=7.7, 1.2 Hz, 1H), 7.11 (ddd, J=11.9, 8.2, 1.0 Hz, 1H), 4.54 (d, J=10.1 Hz, 1H), 4.34-4.23 (m, 1H), 4.26-4.17 (m, 1H), 4.16 (d, J=10.2 Hz, 1H), 4.10 (d, J=8.5 Hz, 1H), 3.71 (d, J=20.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 160.59 (d, JCF=247.0 Hz), 130.50 (d, JCF=8.7 Hz), 128.72, 124.69 (d, JCF=3.3 Hz), 124.45 (q, JCF=281.8 Hz), 124.43 (d, JCF=11.9 Hz), 116.66 (d, JCF=22.7 Hz), 83.70 (q, JcF=32.1 Hz), 78.17 (d, JCF=3.1 Hz), 77.63. 54.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH3:24]
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a stirred solution of 2 g (6.44 mmol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in 40 mL of DMF at 0° C., 283 mg (7.09 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.37 g (9.66 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc 2:1, yielding 0.79 g (38%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+) and 0.71 g (34%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](C)[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:18][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(Br)c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C2C3=C(COCC3=O)NC3=C2C(=O)OC3)cc1Br
Temperature: -10 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
The product from Example 68A (0.63 g, 1.6 mmol) in chloroform (10 mL) under a nitrogen atmosphere was treated with pyridine (0.16 mL, 1.9 mmol) and pyridinium tribromide (0.57 g, 1.8 mmol) at −10° C. After stirring at −10° C. for 2 hours, the mixture was allowed to warm to ambient temperature and then was treated with 1M HC1 and extracted with chloroform. The chloroform layer was dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 1 hour and cooled to ambient temperature. Purification of the residue by chromatography on silica gel eluting with 10% methanol in dichloromethane provided the title compound (0.30 g).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:31])([F:32])[F:30])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:39][CH2:38]1
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2cc3c(cn2)ncn3-c2cc(OCc3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 6, 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) and 200 mg of 1-methylpiperazine in 5 ml dichloromethane yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17]OCC)[O:11][C:10]3[C:21]4[C:26]([CH:27]=[CH:28][C:9]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].[BH4-].[Na+].Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]#[N:15])=[C:12]([NH:16][CH3:17])[O:11][C:10]3[C:21]4[C:26]([CH:27]=[CH:28][C:9]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: CCOC=NC1=C(C#N)C(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1=C(C#N)C(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Temperature: 0 °C

Procedure:
4-(4-Chloro-3-nitrophenyl)-2-ethoxymethyleneamino-4H-naphtho[1,2-b]pyran-3-carbonitrile (4.3 g) was dissolved in tetrahydrofuran (70 ml), and to this solution, with stirring, was added sodium borohydride (2.7 g), in portions. After one hour the suspension was cooled in ice-water and 1 molar hydrochloric acid (20 ml) was added dropwise, followed by water (200 ml). A yellow product was filtered off, washed with water and dried. This material was dissolved in hot chloroform and passed down a chloroform--`flash silica` column. Fractions containing product were bulked, evaporated to dryness, and triturated with ether to give 4-(4-chloro-3-nitrophenyl)-2-methylamino-4H-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 278.5°-279° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:13](O)=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.O1CCCC1.Cl>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:13]([NH:23][CH3:21])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(O)c(Br)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Yield: 100 %

Procedure:
(−)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoic acid (10) (1.50 kg, 4.44 moles), 1,1′-carbonyldiimidazole (1.08 kg, 6.66 moles) and N,N-dimethylformamide (3 mL) were mixed together at ambient temperature. Once the activation reaction was deemed complete, 2 M methylamine solution in tetrahydrofuran (5.5 L, 11.1 moles) was added at a rate that maintained the temperature below 30° C. The mixture became homogeneous as the reaction reached completion. A solution of 1 N hydrochloric acid solution (15.4 kg) was added to reach pH 3 or less. The acidification precipitated the product. The product was filtered, washed with water and vacuum dried at 60° C. overnight to give (−)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (9) (1.56 kg, 4.44 moles, 97% purity).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]#[C:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I.C(#N)C>[C:9]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4])#[C:10][CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccccc1I
Reactant: C#CCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 2-iodoaniline (500 mg, 2.28 mmol), 1-pentyne (0.27 mL, 2.74 mmol), bis(triphenylphosphine)palladium (II) chloride (77 mg, 0.11 mmol), copper iodide (21 mg, 0.11 mmol), triethylamine (0.95 mL, 6.84 mmol), and acetonitrile (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was stirred in diethyl ether and filtered. The filtrate was concentrated under reduced pressure to afford 0.25 g of 2-pent-1-ynylaniline.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH:10]1[CH2:13][CH:12]([O:14][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH2:11]1
Reactant: OC1CNC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of tert-butylchlorodimethylsilane (12.01 g, 79.69 mmol) in DCM (20 mL) was added dropwise to a stiffed solution of azetidin-3-ol hydrochloride (CAS no. 18621-18-6) (8.73 g, 79.69 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (34.1 mL, 199.22 mmol) in DCM (20 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (11.1 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.87 (9H, m), 2.80 (1H, s), 3.57-3.61 (2H, m), 3.67-3.71 (2H, m), 4.57-4.64 (1H, m).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[C:10]=2[F:35])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[F:35][C:10]1[C:11]([CH2:25][NH:26][CH3:27])=[CH:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2C#N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-4-fluoro-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (476 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 265 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: C=CCC(CC(=O)c1ccc(OC)nc1)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-1-(6-methoxy-pyridin-3-yl)-hex-5-en-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an off-white foam, MS (ESI−): m/z=344.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:10][CH:9]2[NH2:20])[CH:7]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C@@H:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C@@H:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]5[N:10]=[C:11]([C:14]6[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=6)[CH:12]=[CH:13][N:20]=5)[CH:7]=4)=[O:40])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH2:28][CH2:29]1
Reactant: CN1CCN([C@H]2CCc3cc(C(=O)Cl)ccc32)CC1
Reactant: Cc1ccc(N)cc1N1C=CC(c2cccnc2)=NC1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CC[C@@H]3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (681 g, 2.46 mol, 1.1-fold) was dissolved in pyridine (3 L). (1S)-1-(4-Methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carbonyl chloride hydrochloride (1325 g, the actual maximum content of 626 g, equivalent to 2.235 mol, 1-fold) was added slowly within 30 minutes with stirring. The solution turned very hot since the reaction was severe but there was no need to have it cool down. After the solution was stirred overnight at room temperature, the reaction solution was added to 2 N aqueous solution of sodium hydroxide (2 L) with stirring, immediately followed by addition of methylene dichloride (2 L). After being stirred for a while, the solution was transferred to a 5 L separatory funnel and then methylene chloride layer was separated. The water phase was extracted with methylene chloride (2×500 mL). The extracts were pooled, dried over anhydrous magnesium sulfate, and then concentrated. The residue was dissolved in methylene dichloride and then purified by silica gel column chromatography using methylene chloride/5% methanol/1% triethylamine as eluent. The fractions containing the desired product were pooled, and concentrated under reduced pressure. The residue was dissolved in 1 L of warm ethyl acetate and crystals were precipitated after stirring. The solid was collected by filtration and dried in vacuum at 50° C. to obtain the title product (617 g, 53% total yield of the three steps). MS (M+1)=520.27.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.S(Cl)(Cl)=O.[NH3:33]>CO>[CH3:26][C:4]1([CH3:27])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH2:33])=[O:25])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Reactant: N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(N)=O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (Step A of Example 185) and thionyl chloride followed by ammonia in MeOH. Yield: 5.3 mg (11%).