Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:7]=1.Br[CH2:25][CH:26]=[CH:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:25][CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)[CH:7]=1
Reactant: Clc1cc(Cl)cc(C=CCBr)c1
Reactant: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1
Product: COC(=O)CCc1cccc(CN(CC=Cc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1

Procedure:
Following the procedure described in Step A of Example 2, 3-[3-(benzenesulfonylamino-methyl)-phenyl]-propionic acid methyl ester was alkylated with 1-(3-bromo-propenyl)-3,5-dichloro-benzene to provide the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, 2H), 7.63 (m, 1H), 7.55 (m, 2H), 7.22 (m, 2H), 7.07 (m, 3H), 6.93 (s, 2H), 6.11 (d, 1H), 5.77 (m, 1H), 4.34 (s, 2H), 3.87 (d, 2H), 3.66 (s, 3H), 2.87 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][C:15]=2[CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][C:15]=2[CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) in MeOH (2 mL) and dioxane (2 mL) was added 1N NaOH aq solution (2.0 mL), and the mixture was stirred at ambient temperature for 3 hours. The pH value of the mixture was adjusted to 7 with 1N HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid and the crude product was used in next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.[N-:47]=[N+:48]=[N-:49].[Na+]>C(Cl)(Cl)(Cl)Cl>[N:47]([CH2:19][C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:8]=1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
In a 50 mL round bottom flask, 7-fluoro-1-(2-fluoro-phenyl)-3-methyl-1H-quinolin-4-one (1.20 g, 4.42 mmol), N-bromosuccinimide (0.787 g, 4.42 mmol) and V65 [2,2′-azobis(2,4-dimethylvaleronitrile)](0.33 g, 1.33 mmol) were combined with carbon tetrachloride (35.0 mL). The reaction mixture was heated to reflux for 5 hr. The reaction was concentrated to dryness and the crude (containing 3-bromomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one) was redissolved in DMF (10.0 mL). To this reaction mixture was added sodium azide (1.44 g, 22.1 mmol) and the reaction was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was evaporated to dryness and purified by flash chromatography using 40% ethyl acetate-hexanes to afford 3-azidomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one (740 mg, 53.6%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:49]=[CH:48][C:42]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[C:41]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:49]=[CH:48][C:42]([C:43]([N:45]([CH3:46])[CH3:47])=[O:44])=[C:41]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:51])=[O:52])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N(C)C
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)ccc1C(=O)N(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2-(isopropylsulfonyl)-N,N-dimethylbenzamide (Intermediate 255), the title compound was obtained as brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]1=[O:28].[H][H].CCOCC>[Pt].C(OCC)(=O)C.C(Cl)Cl>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2=[O:28])[CH:4]=1
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O

Procedure:
A mixture of isopropyl 3-(2-chloro-4-fluoro-5-nitrophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (34.8 g, 0.0835 mol) and 5% platinum on carbon (3.48 g) in ethyl acetate is hydrogenated until about 90 psi of hydrogen is taken up. The reaction mixture is then filtered and concentrated in vacuo to obtain a foam. Column chromatography of the foam using silica gel and 10% to 20% ether in methylene chloride solutions gives a yellow foam which contains two compounds. A mixture of the foam and 5% platinum on carbon (3.5 g) in ethyl acetate is hydrogenated until 5 psi of hydrogen is taken up. The reaction mixture is then filtered and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[Br:23][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(Br)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 37.9 g. (0.174 m.) of the compound of Example I, C., 30 g. (0.174 ml.) of p-bromoaniline and 500 ml. of ethanol was stirred and refluxed overnight. After concentrating in vacuo the residue was recrystallized from 500 m. of MeOH to give 55 g. m.p. 347°-349° .
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:21][C:14]([CH3:20])([CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:22]1[CH2:23][CH2:24][CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Yield: 21.3 %

Procedure:
Ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (8.2 g, 29 mmol) was treated according to a modification of the method described in Part B of Example 8. Prior to the addition of trimethyl orthobutyrate (5.3 g, 36 mmol) and pyridinium p-toluenesulfonate (0.10 g, 0.40 mmol), the reaction was heated at reflux for ten minutes. During the work-up procedure, the solution was dried over potassium carbonate. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol containing 3 mL concentrated ammonium hydroxide per liter of eluent) to provide 2.1 g of ethyl 2,2-dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: CCO
Reactant: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 6-chloro-7-hydroxychroman-4-carboxylic acid (99 g, 433 mmol) in ethanol (650 mL) was added sulfuric acid (1.2 mL) and the reaction was stirred at 60° C. for 24 hours. The reaction was cooled to ambient temperature and the resulting solids were removed by filtration and discarded. The filtrate was diluted with ethyl acetate (700 mL), washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a solvent system of 20% ethyl acetate/hexanes to give ethyl 6-chloro-7-hydroxychroman-4-carboxylate (46 g, 41%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.I[CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:35][CH:36]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OCCCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium carbonate (0.19 g, 1.38 mmol) was added to a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one, from Ex. 1, Step 8 (0.50 g, 1.15 mmol) in DMF (30 ml) followed by 1-iodo-4,4,4-trifluorobutane (328 mg, 1.38 mmol). The reaction mixture was heated at 80° C. overnight. TLC showed very little conversion to starting material; 656 mg (2 eqv.) 1-iodo-4,4,4-trifluorobutane and 380 mg (2 eqv.) K2CO3 were added and heating continued for one hour. After cooling to rt, water was added and the product extracted with EtOAc (×3). The combined organic extracts were washed with brine (×2), dried (Na2SO4), filtered and concentrated. Flash chromatography (heptane:EtOAc gradient) afforded 250 mg (40%) of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)c(Cl)c1
Yield: 56.1 %

Procedure:
Pyrrolidine (22.0 mL, 0.255 mol) was added to a suspension of intermediate 14, 2-chloro-4-hydroxybenzaldehyde (30.8 g, 0.196 mol) in dichloromethane (620 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (65.8 g, 0.295 mol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (600 mL) and dichloromethane (600 mL) were added. The reaction mixture was acidified with concentrated HCl to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with EtOAc (2×500 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CHCl3 (3×500 mL). The organic layer was dried with anhydrous Na2SO4 (50 g). The solvent was evaporated in vacuo. The obtained oil was refluxed in Et2O (400 mL) for 1 h. Then hexane (200 mL) was added, and the mixture was cooled. The formed residue was separated by filtration and dried. 1H NMR spectrum showed the presence of acetic acid (2.3% w/w). The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL), and a solution of NaOH (0.4 g) in water (4 mL) was added. The product was extracted form the organic layer. The extract was dried with anhydrous Na2SO4 (50 g), evaporated, and coevaporated with dioxane. The title compound (23.5 g, 0.11 mol, 56%) was obtained as a pale-yellow powder. LC/MS data: 212.0 and 214.0 (M+H)+ (calculated for C22H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.73 (br.s., 1H, OH); 7.24 (d, 1H, J=8.3 Hz, Ar—H); 6.78 (d, 1H, J=2.4 Hz, Ar—H); 6.70 (d.d., 1H, J1=8.3 Hz, J2=2.4 Hz, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.70 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]4[O:24][CH2:23][CH2:22][O:18]4)[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2ccc(C=Cc3cccc(C4OCCO4)c3)nc2c1

Procedure:
A mixture of 3-(2-(7-chloroquinolin-2-yl)ethenyl)benzaldehyde (step 1) (938 mg, 3.19 mmoles), ethylene glycol (200 μL, 1.15 equiv.), p-toluene-sulfonic acid (296 mg, 0.5 equiv.) and toluene (1.5 mL) was heated at reflux overnight. 25% aqueous NH4OAc was then added and the mixture extracted with EtOAc. Flash chromatography of the residue on silica with EtOAc:hexane 20:80 afforded the title compound.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]=[C:23]1[CH3:39])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]CC)=[O:7])C>C1COCC1.[OH-].[Na+]>[CH3:39][C:23]1[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:4]([OH:40])=[O:3])[C:6]([OH:8])=[O:7])[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:24]=1
Reactant: CCOC(=O)C(CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1)(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCC(C(=O)O)(C(=O)O)c1ccccc1
Yield: 102.7 %

Procedure:
(Scheme 4 (S)) A solution of starting material 2-[5-(2-methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl-malonic acid diethyl ester (630 mg, 1.17 mmole) in THF (18 ml) and Sodium hydroxide (2N) (8 ml) was let stirred at 80° C. for 18 hrs. The next day, analysis by TLC indicated no significant change in the reaction. The THF solvent was removed by rotorvap. The residue was diluted in Methanol (20 ml). The reaction solution was let stirred under reflux for 2 hrs. Analysis by TLC indicated consumption of starting material. The organic solvent was removed by rotorvap. The residue was diluted with water (20 ml). The aqueous layer was extracted Diethyl Ether (2×20 ml). The organic layers were combined and extracted with Sodium Hydroxide (10%) (2×10 ml). The basic aqueous layers were combined and acidified with Hydrochloric acid (3N) to pH=1, then extracted with dichloromethane (2×20 ml). The organic layers were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo to provide product as a white solid (580 mg, quantitative yield). Mass Spec: 483.54 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Br[CH2:23][CH:24](OCC)OCC>CC(O)C>[Br:8][C:6]1[N:7]2[CH:23]=[CH:24][N:1]=[C:2]2[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Reactant: CCOC(CBr)OCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3ccnc23)CC1
Yield: 23.4 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(3-amino-5-bromopyrazin-2-yl)piperazine-1-carboxylate (4.0 g, 11.2 mmol), 2-bromo-1,1-diethoxyethane (3.3 g, 16.5 mmol) and absolute propan-2-ol (200 mL). The resulting solution was refluxed under N2 for 12 h. Work-up: the resulting crystalline solid was collected by filtration, washed with EtOAc (100 mL), and dried to afford 1.0 g (23%) of the product as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:36])([F:35])[C:11]([CH2:30][NH:31][CH2:32][CH2:33][CH3:34])([OH:29])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:32]([N:31]([CH2:30][C:11]([OH:29])([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]([F:36])([F:35])[F:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:33][CH3:34]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[C:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=3[F:36])[CH:18]=2)[NH:13][CH:12]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([N:29]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:23]=3[F:36])[CH:18]=2)[N:13]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(C)=O)c3c2)c1F
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C(C)=O)cn3S(=O)(=O)CCC)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
TEA (0.0163 mL, 0.117 mmol) and propane-1-sulfonyl chloride (0.00882 mL, 0.0779 mmol) were added to N-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.195 mL, 0.0390 mmol) in DCM (0.4 mL). The solution was stirred at room temperature for 16 hours before concentration under reduced pressure. The resulting residue was purified via column chromatography (2% MeOH/DCM) to afford impure N-(3-acetyl-1-(propylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.020 g, 0.0308 mmol, 79.1% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[CH3:1][C:2]1[N:7]2[C:8]([CH2:11][S:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n12
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cccc2ncc(CSc3ccc(N)cc3)n12
Yield: 103.1 %

Procedure:
A mixture of 5-methyl-3-[(4-nitrophenylthio) methyl]imidazo[1,2-a]pyridine (1.80 g), reduced iron (1.68 g) and calcium chloride (0.33 g) in 15% water-containing ethanol (54 ml) was heated to reflux for 24 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give 4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]aniline (1.67 g) as yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[CH:42]([OH:44])=[O:43].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:42]([OH:44])=[O:43].[CH:42]([OH:44])=[O:43].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CN1CCNCC1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CN1CCN(CCOc2cccc(-c3cc(C(=O)N4CNC(=O)C4)nn3-c3cccc(Cl)c3)c2)CC1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and 1-methylpiperazine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 46 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20]([OH:22])=O)[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.Cl.Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([N:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[C@@H:40]([CH3:45])[CH2:39]2)[CH3:37])[CH2:31][CH2:30]1>>[OH:44][C@H:41]1[CH2:42][CH2:43][N:38]([C@@H:36]([CH3:37])[CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:22])[CH2:34][CH2:33]2)[CH2:39][C@@H:40]1[CH3:45]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 106 (see example 55) and amine 56.