Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:41][CH2:42][N:37]3[CH2:36][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(C(c2ccc(O)cc2)c2cccc3c2CCCC3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)c2cccc3c2CCCC3)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (300 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), 1-(2-chloroethyl)piperidine hydrochloride (300 mg, 0.0015 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give the title compound of formula I. Yield 218 mg. (55.89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(OCC)(=O)C.O>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of ethyl acetate were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate dissolved in 9.3 g of water. The reaction was carried out for 3 hours with stirring at 15°-20 C. Thereafter, 100.4 g of acetic acid and 75.3 g of water was added to the concentrate and the mixture was stirred for one hour at 15°-20.C. Precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:16])[C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[C:1]1([CH2:7][O:8][C:9](=[O:16])[C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][O:13][C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(CCO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester (1.11 g), in dichloromethane in an ice bath, was added dimethylaminopyridine (0.72 g) followed by a solution of decanoyl chloride (0.95 g) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours and was filtered. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with dichloromethane to afford 1.4 g (74.5%) of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid phenylmethyl ester. A portion was evaporatively distilled to give an analytical sample as a colorless oil: bp 190° C./0.15 mm; IR (CHCl3) 1720 (C=O) and 697 cm-1 (Ph); NMR (CDCl3) δ 0.87 (t, 3, CH3), 1.25-1.60 (m, 20, CH2 and CH3), 1.93 (t, 2, CH2), 2.23 (t, 2, CH2), 4.11 (t, 2, CH 2), 5.11 (s, 2, CH2) and 7.33 (s, 5, Ph); MS m/e 376 and 91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: ClCCc1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
In a 250-mL round bottom flask equipped with overhead stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, 2-(4-chlorophenyl)ethanol (40.011 g, 255 mmol) and N,N-dimethylacetamide (1.197 mL, 12.77 mmol) were heated to 55° C. Thionyl chloride (19.58 mL, 268 mmol) was added slowly and significant off-gassing was observed. After the addition was complete the resulting dark-brown solution was stirred at between 60 and 64° C. for 1.5 hours and then allowed to cool to room temperature and stirred overnight to give the title compound as a dark-brown oil (47.060 g, including DMA and thionyl chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:22][C:21]([CH2:25][F:26])([CH2:23][F:24])[CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([Cl:47])[CH:41]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:48][C@H:49]1[CH2:54][CH2:53][C@H:52]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])[CH2:51][CH2:50]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([Cl:47])[CH:41]=4)[C@H:13]([C:14]([NH:48][C@H:49]4[CH2:50][CH2:51][C@H:52]([C:55](=[O:56])[N:57]([CH3:58])[CH3:59])[CH2:53][CH2:54]4)=[O:39])[N:18]([C@H:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:16]([OH:15])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]43[CH2:20][C:21]([CH2:25][F:26])([CH2:23][F:24])[CH2:22]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N2[C@@H]1[C@H](c1cc(F)cc(Cl)c1)[C@@]1(C(=O)Nc3cc(Cl)ccc31)C21CC(CF)(CF)C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](N)CC1
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)[C@H]2[C@H](c3cc(F)cc(Cl)c3)C3(C(=O)Nc4cc(Cl)ccc43)C3(CC(CF)(CF)C3)N2[C@H](c2ccccc2)[C@@H](O)c2ccccc2)CC1

Procedure:
The compound (339 mg, 0.50 mmol) obtained in Step 1 of Example 164 and trans-4-amino-N,N-dimethylcyclohexanecarboxamide (144 mg, 0.85 mmol) were used as starting materials and treated in the same way as in Step 1 of Example 20 to give 178 mg (42%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[CH2:26][C:27](OC)=[O:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[CH2:26][CH2:27][OH:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1F
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOC
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(CCO)c1ccccc1F
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Of the compound from Example 93A, 39 mg (0.07 mmol) were dissolved in 2 ml of 1,2-dimethoxyethane and admixed at room temperature in succession with 4.1 mg (0.11 mmol) of sodium borohydride and with 0.6 mg (0.014 mmol) of lithium chloride. Subsequently the mixture was stirred at 85° C. for 16 h. For work-up, 10 ml of saturated aqueous sodium potassium tartrate solution were added and the mixture was extracted with three times 10 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [Method 19]. This gave 19 mg (49% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][C:4]=1[B:12]([OH:14])[OH:13].[CH3:15][NH:16][CH3:17].O1CCCC1.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:10])[N:16]([CH3:17])[CH3:15])=[CH:5][C:4]=1[B:12]([OH:14])[OH:13]
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N(C)C)cc1B(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude 2-methoxy-5-carboxyphenylboronic acid (370 mg) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added 2.0M-dimethylamine/tetrahydrofuran solution (1.9 ml), 1-hydroxybenzotriazole dihydrate (725 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (579 mg). The mixture is stirred at room temperature for 3 hours, and thereto is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=19:1) to give 2-methoxy-5-dimethylcarbamoylphenylboronic acid (210 mg). MS (m/z): 224 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].O=P(Cl)(Cl)Cl>N1C=CC=CC=1.CCOC(C)=O>[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:15][C:12]1[S:13][CH:14]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:11]=1)=[O:26]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
A stirring solution of 4-(3-nitrophenyl)-thiazol-2-ylamine (11) (2.21 g, 10 mmol) and suberic acid monomethyl ester (13) (1.88 g, 10 mmol) in dry pyridine (20 ml) was cooled to −15° C. and POCl3 (1.2 ml, 13 mmol) was added dropwise over 30 minutes. After stirring for another 1 hour at same temperature, the reaction mixture was diluted with EtOAc and washed thoroughly with 1N HCl solution and brine. The organic phase was dried over Na2SO4. The solvent was removed by rotary evaporation. The crude solid was washed with EtOAc to give compound 14 (2.40 g, 61.5%). 1H NMR (400 MHz, DMSO-d6) δ12.3 (1H, s), 8.74 (1H, d, J=1.4 Hz), 8.35 (1H, d, J=7.1 Hz), 8.18 (1H, d, J=7.8 Hz), 7.93 (1H, s), 7.74 (1H, t, J=7.9 Hz), 3.58 (3H, s), 2.46 (2H, t, J=7.5 Hz), 2.30 (2H, t, J=7.3 Hz), 1.61 (2H, t, J=6.5 Hz), 1.53 (2H, t, J=6.8 Hz), 1.30 (4H, brs). 13C NMR (100 MHz, DMSO-d6) δ172.1, 158.8, 148.7, 146.7, 136.2, 132.1, 130.8, 122.7, 120.5, 110.8, 51.6, 35.2, 33.6, 28.6, 28.5, 24.8, 24.6.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16].[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:15][CH3:16])=[C:2]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1c(Br)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1c(N2CCCC2=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.5 %

Procedure:
An oven-dried Schlenk tube was charged with 2-bromo-4-tert-butyl-6-nitroanisole (500 mg, 1.74 mmol), 2-pyrrolidinone (158 μL, 2.09 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol) and Cs2CO3 (795 mg, 2.44 mmol). The tube was capped with a rubber septum, purged with argon and 1,4-dioxane (7 mL) was then added through the septum via a syringe. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at 100 C for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and crude product was purified by column chromatography (2:1 hexane-EtOAc) to give 1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-pyrrolidin-2-one (150 mg, 30%).
Reaction SMILES: N1(C2C=CC(CC(N3CCN(C(C)CC4C=CC5C(=O)OCC=5C=4)CC3)=O)=CC=2)C=NN=N1.Cl.[N:35]1([C:41](=[O:54])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH:53]=[N:52][N:51]=[N:50]3)=[CH:45][CH:44]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O=[C:56]1[CH2:65][CH2:64][C:63]2[CH:62]=[C:61]([C:66]#[N:67])[CH:60]=[CH:59][C:58]=2[CH2:57]1>>[N:49]1([C:46]2[CH:45]=[CH:44][C:43]([CH2:42][C:41]([N:35]3[CH2:40][CH2:39][N:38]([CH:56]4[CH2:65][CH2:64][C:63]5[CH:62]=[C:61]([C:66]#[N:67])[CH:60]=[CH:59][C:58]=5[CH2:57]4)[CH2:37][CH2:36]3)=[O:54])=[CH:48][CH:47]=2)[CH:53]=[N:52][N:51]=[N:50]1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Agent: CC(Cc1ccc2c(c1)COC2=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Agent: Cl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1)C2

Procedure:
6-(4-{[4-(1H-Tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile was prepared in an analogous fashion to that described above for the synthesis of 5-[2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)propyl]-2-benzofuran-1(3H)-one starting from 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride and known compound 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Ralf Heim, et al. J. Med. Chem. 2008, 51(16), 5064-5074). LC/MS: [(M+1)]+=428.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:31](=[O:33])[CH3:32])[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cc3cnn(C4CCCCO4)c3cc2NC2CCOCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1)C1CCOCC1
Yield: 82.4 %

Procedure:
To a solution of 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-amine (1.87 g, 4.59 mmol) in THF (30 mL) is added acetyl chloride (0.39 mL, 5.48 mmol) and K2CO3 (760 mg, 5.50 mmol). After the reaction mixture is heated to reflux for 30 min, H2O (20 mL) and EtOAc (30 mL) are added. The organic phase is separated, washed with saturated aqueous NH4Cl, dried and concentrated to give the product (1.7 g, 82.4% yield). MS (m/z): 450.2 (M+H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=O)[CH:13]=[CH:12]2>>[Br:3][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([Br:6])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1ccc2cccc(Br)c2[nH]1
Product: Brc1ccc2cccc(Br)c2n1
Temperature: 125 °C
Yield: 62.8 %

Procedure:
A mixture of phosphorus oxybromide (1.59 g, 5.55 mmol) and 8-bromo-2(1H)-quinolinone (0.250 g, 1.11 mmol) was heated at 125° C. for 2 h before being poured onto ice. The resulting precipitate was filtered and crystallized from MeOH to give 2,8-dibromo-quinoline (0.2 g, 64%) as colorless prisms. MS (ESI, pos. ion) m/z: 287.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:11][C:7]1[CH:8]=[C:2]([Cl:1])[C:3]([O:9][CH3:10])=[CH:4][C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(N)ccc1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1Cl
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 4-chloro-3-methoxyaniline (1.0 equivalent) dissolved in CH2Cl2 (15 volumes) at 5° C. was treated portion wise with N-bromosuccinimide (1.03 equivalents), warmed to 20° C. and mixed for 5 minutes. A 5% aqueous Na2SO3 solution (10 volumes) was added and the mixture was stirred for 10 minutes. The layers were separated and the organic layer was washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with a minimal volume of heptane and the solid was collected by filtration and dried to constant mass (80% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=N)C.ON1C2C=CC=CC=2N=N1.Br.[CH3:46][C:47]1[CH:48]=[C:49]([OH:56])[CH:50]=[C:51]2[C:55]=1[CH2:54][NH:53][CH2:52]2.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:53]1[CH2:52][C:51]2[C:55](=[C:47]([CH3:46])[CH:48]=[C:49]([OH:56])[CH:50]=2)[CH2:54]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Cc1cc(O)cc2c1CNC2
Agent: Br
Agent: CCN=C=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cc(O)cc(C)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
2,4-Bis-benzyloxy-5-isopropenyl-benzoic acid (248 mg, 0.66 mmol), 1-[3-(dimethylamino)propyl)]-3-ethylcarbodiimide hydrochloride (127 mg, 0.66 mmol) and 1-hydroxybenztriazole (89 mg, 0.66 mmol) were dissolved in DMF (5 mL). After 20 minutes, 7-methyl-2,3-dihydro-1H-isoindol-5-ol hydrobromide (152 mg, 0.66 mmol) and triethylamine (0.14 mL, 0.99 mmol) were added. After a further 3.5 hours the mixture was concentrated in vacuo and the residue was treated with 1N hydrochloric acid and ethyl acetate. The aqueous phase was removed, brine was added and the title compound was collected by filtration as a grey solid (168 mg, 57%). 1H NMR (DMSO-d6) 9.30 (0.47H, s), 9.24 (0.53H, s), 7.48-7.25 (10H, m), 7.09 (0.47H, s), 7.08 (0.53H, s), 6.99 (0.47H, s), 6.98 (0.53H, s), 6.56 (0.47H, s), 6.50 (0.53H, s), 6.48 (0.47H, s), 6.44 (0.53H, s), 5.24 (0.47H, s), 5.22 (0.53, s), 5.18 (2H, s), 5.10-5.07 (2H, m), 4.70 (0.47H, s), 4.61 (0.53H, s), 4.46 (0.47H, s), 4.36 (0.53H, s), 2.17 (1.41H, s), 2.04 (3H, s), 1.99 (1.59H, s). MS: [M+H]+ 506.
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[N+:14]=[N-:15])[C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=[N+]=[N-])c1ccc(Cl)cc1
Yield: 83.2 %

Procedure:
A solution of 4-acetamidobenzenesulfonyl azide (1.43 g, 5.96 mmol) and methyl 2-(4-chlorophenyl)acetate (1 g, 5.42 mmol) in acetonitrile (27 mL) was cooled to 0° C. DBU (0.907 g, 0.891 mL, 5.96 mmol) was then added dropwise to the reaction mixture. The mixture was allowed to stir over night, after which it was passed through a plug of silica and purified by column chromatography (EtOAc) to give methyl 2-(4-chlorophenyl)-2-diazoacetate (0.95 g, 83%) as a solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[F:21][C:22]([F:33])([F:34])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:29])=[CH:26][CH:25]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=NC(=O)c1ccc(OC(F)(F)F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-(trifluoromethoxy)-benzoyl chloride, there is obtained ethyl N-[p-(trifluoromethoxy)-benzoyl]-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 454 (1), 425 (11), 194 (100), 189 (40);
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[CH:12][CH:11]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[CH:12][CH:11]=2)=[O:8])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(O)c1cc[nH]n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1H-Pyrazole-3-carboxylic acid (560 mg, 5 mmol) was dissolved in methanol (62 ml) and (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (1.39 g, 5 mmol) was added. The solution was cooled to 0° C. and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.8 g, 6.5 mmol) dissolved in 5 ml methanol was added drop-wise to the reaction mixture in 1 hour. The reaction mixture was stirred at 0° C. for two hours then overnight at room temperature. The solvent was evaporated, the residue was dissolved in dichloromethane and adsorbed on silicagel.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37])#[CH:28].[Cl:40][C:41]1[N:46]=[C:45](Cl)[C:44]([CH3:48])=[CH:43][N:42]=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[Cl:40][C:41]1[N:46]=[C:45]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:44]([CH3:48])=[CH:43][N:42]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Temperature: 120 °C

Procedure:
PPh3 (31 mg, 0.12 mmol), PdCl2(PPh3)2 (84 mg, 0.12 mmol), Et3N (0.67 mL, 4.8 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (0.25 g, 1.4 mmol) were added to a solution of 2,4-dichloro-5-methylpyrimidine (0.20 g, 1.2 mmol) in anhydrous DMF (5.0 mL). The solution was degassed with nitrogen for 10 minutes before the addition of CuI (23 mg, 0.12 mmol). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then diluted with EtOAc (30 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure and the resulting residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-35% EtOAc in petroleum benzine 40-60° C.) to give the title compound K7 as a yellow solid (0.28 g, 78%); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.46-7.40 (m, 1H), 7.39-7.31 (m, 2H), 3.93 (s, 2H), 3.71 (s, 3H), 2.45 (s, 3H). LCMS-A: rt 5.993 min; m/z 301 [M+H]+.