Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]2[CH:17]([CH2:18][N:19]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:20]2)[C:16]1=[O:38])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:31]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:38])[CH2:20]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OC1CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(O)CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
37 cm3 of 1.38 molar 2-methoxyphenylmagnesium bromide solution in tetrahydrofuran are added to a solution containing 2.4 g of (3aRS,5RS,7SR,7aRS)-5-acetoxy-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone in 50 cm3 of tetrahydrofuran at 4° C. The reaction mixture is stirred at room temperature for 18 hours, treated with 150 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of water and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 27 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 35 cm3 fractions. Fractions 8 to 15 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.65 g of (3aRS,4RS,5RS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained in the form of a yellow foam.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[OH:15])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O>C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:15][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][C@H:5]1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: COc1ccccc1O
Reactant: CN(C)C[C@@H]1CCc2ccccc2[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccccc1O[C@@H]1c2ccccc2CC[C@H]1CN(C)C
Reaction time: 2 h

Procedure:
A mixture of 8.21 g (0.04M) of TRANS-1,2,3,4-tetrahydro-2-(N,N-dimethylaminomethyl)naphthalen-1-ol, 11.54 g (0.044M) of triphenyl phosphine, 5.46 g (0.044M) of 2-methoxyphenol and 100 ml of benzene was stirred and a solution of 7.83 g (0.004M) of 95% diethyl azodicatrboxylate in 25 ml of benzene was added dropwise over 45 minutes. After 2 hours, the mixture was filtered and extracted with cold 3% hydrochloric acid. The acid extracts were made basic with dilute sodium hydroxide and the oil which separated was extracted into ether. The solvent was removed and the residual oil chromatographed on silica gel.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[CH:75]=[CH:74][C:73]([N:76]2[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]2)=[CH:72][C:54]=1[C:55]([NH:57][C:58]1[N:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[C:66]([CH3:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O>[CH3:71][C:66]1[CH:65]=[C:64]([C:61]2[CH:60]=[N:59][C:58]([NH:57][C:55]([C:54]3[CH:72]=[C:73]([N:76]4[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:74]=[CH:75][C:53]=3[NH:52][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH:11]=3)=[O:56])=[N:63][CH:62]=2)[CH:69]=[CH:68][C:67]=1[CH3:70]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(C(=O)NCCOCCO)c3)nc2)cc1C
Yield: 8.8 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (227.1 mg, 0.90 mmol, 3.00 equiv) in N,N-dimethylformamide (6 mL), HATU (397.5 mg, 1.05 mmol, 3.50 equiv), N,N-diisopropylethylamine (192.8 mg, 1.49 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.30 mmol, 1.00 equiv) and the resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 100 mL of water and the resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 2×50 mL of brine and then dried over sodium sulfate. The solids were filtered out and the resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 16.8 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.34 (s, 1H), 11.24 (s, 1H), 8.71˜8.68 (m, 3H), 8.38 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.04˜7.99 (m, 2H), 7.66˜7.58 (m, 1H), 7.47˜7.38 (m, 1H), 7.28˜7.19 (m, 2H), 7.15 (d, J=6.3 Hz, 1H), 4.42 (s, 1H), 3.56˜3.44 (m, 9H), 3.31 (m, 4H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 637 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(Cl)c1
Yield: 44.4 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (44%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[C:2]1=[O:3].S(Cl)([Cl:17])=O>ClCCl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([Cl:17])=[O:14])[C:2]1=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2oc1=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2oc1=O

Procedure:
Coumarin-3-carboxylic acid (2.1 g, 10 m mole) was suspended in dry dichloromethane (10 ml) and heated at reflux for 2 h with thionyl chloride (5 ml). After this time a small amount of insoluble material was filtered off and petroleum ether 60°-80° C. (35 ml) was added to the filtrate. The acid chloride was filtered, washed with ether and dried (1.63 g, 71%), mp 138°-41° C.; νmax (CHCl3) 1790, 1740, 1610, 1570 cm-1 ; δ (CDCl3) 7.30-8.10 (4H, m, phenyls), 8.95 (1H, s, coumarin 4-H).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([C:27]1[C:35]2[N:34]=[C:33]([O:36]CC)[N:32](C(OC(C)(C)C)=O)[C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1)=[O:26]>C1COCC1>[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([OH:26])([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)[C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1
Reactant: c1cnccn1
Reactant: CCOc1nc2c(C(=O)c3c(F)cccc3F)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2cnccn2)c2c(F)cccc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
n-BuLi (0.21 mL, 0.33 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.06 mL, 0.33 mmol) in THF (0.7 mL) at 0° C. and was allowed to stir for 5 minutes. Pyrazine (24 mg, 0.3 mmol) in THF (0.4 mL) was added and the reaction was stirred for an additional 5 minutes and then cooled to −78° C. tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in THF (0.4 mL) was added, the solution was allowed to stir for 5 minutes and then quenched with water. Solution was extracted three times with EtOAc, washed once with brine and concentrated. Crude was purified by reverse-phase HPLC and then taken up in EtOH (3 mL) and HCl (0.1 mL) and heated to 65° C. for 2 hours. Reaction was cooled and concentrated to afford desired product as a pale brown powder.
Reaction SMILES: C1(CCO[C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)CC1.OC1C=CC(C(OC)=O)=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][OH:35]>>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:35][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=1
Reactant: OCCC(F)(F)F
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: COC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCC(F)(F)F)cc1
Yield: 14 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (1.52 g, 9.99 mmol) and 3,3,3-trifluoropropan-1-ol (1.14 g, 9.99 mmol) to give 385 mg of the title compound (white powder, yield: 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:13][CH2:14][C:15]#[N:16].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:37])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:13][CH2:14][C:15]#[N:16]
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of the compound from Example 47 with a purity of 85% (0.21 mmol) were introduced into 14 ml of dichloromethane at 0° C., 59.1 mg (0.24 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 62 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])=[N:11][N:10]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][N:11]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Br)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
ZnCl2 (2.04 g, 15 mmoles) under N2 in THF (100 ml) was added with phenyl lithium (7.5 ml, 15 mmoles; 2M in cyclohexane/ethyl ether 7:3) at 0-4° C. The mixture was stirred at room temperature for 1 hour. 4-Bromo-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (3 g, 7.5 mmoles), prepared as described in example 46, palladium acetate (0.034 g, 0.15 mmole) and triphenylphosphine (0.08 g, 0.3 mmole) were added and the mixture was refluxed for 24 hours, cooled and extracted with a saturated solution of NHCl. The organic phase was extracted again with ethyl acetate, discoloured with charcoal, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: petrolatum/ethyl acetate 6:4). The resultant solid was triturated in ethyl ether, crystallised from acetonitrile (80 ml) and dried overnight to give 1.44 g of the title compound (yield: 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:45]=[CH:44][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:32]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:34]=2)[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:29]1[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:45][CH:44]=3)[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:32]=2)[CH2:27][CH2:28]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 77 %

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine (0.5 g, 1.09 mmol) and other reagents as described in Example 9(e) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.38 (9H, s), 2.45 (2H, m), 3.14 (2H, m), 3.52 (8H, m), 6.71 (1H, brs), 7.01 (2H, s), 7.08 (1H, t), 7.28 (4H, d), 7.89 (4H, d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([Cl:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:24]=[CH:23]2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3cccc(Cl)c3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc2ccc(NC3CCNCC3)nc12

Procedure:
A solution of 4-(8-chloro-quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 3.59 mmol) in 4 M HCl in dioxane (120 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 262.3 [M+H]−.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1([CH3:25])[CH2:24][C:15]2[C:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[C:17]=3[S:23][C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:19]2[CH2:20][CH2:21][C:16]3[C:15]4[CH2:24][C:12]([CH3:11])([CH3:25])[CH2:13][C:14]=4[S:23][C:17]=3[C:18]2=[O:22])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: CC1(C)Cc2sc3c(c2C1)CCNC3=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)Cc2sc3c(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotin-aldehyde (400 mg, 1.5 mmol), 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-9-one (106h) (170 mg, 0.76 mmol), and cesium carbonate (176 mg, 1.5 mmol). Xantphos (40 mg, 0.08 mmol) and Pd2(dba)3 (70 mg, 0.08 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 106i (200 mg, 65%). MS: [M+H]+ 405.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+:15]>CO>[CH3:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:15]
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)ccc1OCC(=O)[O-]
Yield: 99.7 %

Procedure:
20 parts (0.1 mol) of 2-methyl-4-chlorophenoxyacetic acid (MCPA) (94.7%) are melted at 130° C. and reacted with 45 parts (0.1 mol, based on 100%) of 8.9% strength sodium hydroxide solution with simultaneous removal of methanol by distillation. After complete removal of methanol by distillation, 23.5 parts of MCPA-sodium of m.p. 227-230° C. are obtained, containing 80.8% MCPA, which corresponds to a yield of 99.7%.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5.0 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 3 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4). After the solvent was distilled off, the residue was recrystallized from ether to yield 1.11 g (59%, white crystal) of the desired product.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[C:17]4[CH3:23])[C:11]([CH3:24])=[C:10]([F:25])[CH:9]=2)[CH2:5][CH2:4]1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH:3]1([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[N:18]=[C:17]4[CH3:23])[C:11]([CH3:24])=[C:10]([F:25])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]nc(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(c1)c(C)nn2S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 50.1 %

Procedure:
Sodium hydride (60% oil dispersion, 0.008 g) was added to a stirred solution of N-cyclopropyl-3-fluoro-4-methyl-5-(3-methyl-1H-indazol-5-yl)benzamide (Example 121) (0.033 g) in dry DMF (1.5 ml) under nitrogen. After 5 min a solution of 2-thiophenesulphonyl chloride (0.038 g) in DMF (0.75 ml) was added and stirring was continued for a further 2 h. Water (1 ml) and chloroform (10 ml) were added, the mixture was passed through a hydrophobic filter and the solvent was evaporated. The residue was purified by preparative Hplc to give the title compound as a clear glass (0.024 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][C:12]([O:14]CC)=[O:13].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([OH:14])=[O:13])#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(OCC(=O)O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-hydroxybenzonitrile (100 mg, 0.840 mmol) in MeCN (5 mL) was added ethyl bromoacetate (209 mg, 1.26 mmol) and K2CO3 (350 mg, 2.52 mmol). The mixture was stirred at 80° C. for 4 hours until TLC showed completion of the reaction. The mixture was filtered and the filtrate concentrated. NaOH (67 mg, 1.68 mmol) and water:EtOH (1:1, 10 mL) was added to the residue and the mixture stirred at 50° C. for 4 hours. After cooling, the mixture was acidified by 1M HCl, extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was used directly in the next step. LCMS (m/z): 178.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:29][CH:26]2[CH2:28][CH2:27]2)[S:8]1(=[O:25])=[O:24]
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: O=S1(=O)N(CCOCCNC2CC2)c2ccccc2N1c1c(F)cccc1F

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with cyclopropylamine (0.64 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)cyclopropanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.63 g, 57%). HRMS: calcd for C19H21F2N3O3S+H+, 410.13444; found (ESI, [M+H]+Obs'd), 410.1341.