Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([Cl:25])=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[Cl:25][C:21]1[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)=[C:23]([F:24])[CH:22]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F)c1cccc(C(F)(F)F)c1
Yield: 20.2 %

Procedure:
Using N-[6-(3-amino-6-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (181 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (114 mg, 0.60 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (54 mg, 20%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[O:10][CH3:11])[C:3]=1[O:12][CH3:13].[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>O1CCCC1>[CH3:13][O:12][C:3]1[C:4](/[CH:8]=[CH:9]/[O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CO/C=C/c1cccc(Br)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(B(O)O)c1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-bromo-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]benzene (D100) (930 mg, 3.83 mmol) in Tetrahydrofuran (THF) (10 mL) was added BuLi (1.989 mL, 4.97 mmol) dropwise at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 2 hours. Tris(1-methylethyl) borate (1.319 mL, 5.74 mmol) was added to the reaction mixture by syringe at −78° C. Then the reaction was stirred at −78° C. for 30 min, and then warmed to room temperature slowly. Then the reaction was quenched with water. The mixture was extracted with EA (15 mL×3). The combined organic layers was dried over anhydrous sodium sulphate. After filtration and concentration, the crude {2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}boronic acid (D101) (741 mg) was used directly in the next step. MS (ES): C10H13BO4 requires 208.1. found 209.0 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(OCC)(=O)C>CC(C)=O.O.[Cl-].[Na+].O>[C:22]([NH:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:7]([F:15])[CH:6]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cc(F)c(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 0.518 g of 3,5-difluoro-4-morpholinyl-aniline and 0.432 g of sodium bicarbonate in 20 mL of acetone:water (2:1 v/v) at 0° C. was added 0.36 mL of benzyl chloroformate over 2 minutes. After 5.5 hours, the mixture was allowed to warm to ambient temperature and after an additional 2.6 hours, the mixture was added to 25 mL of ethyl acetate and 20 mL of brine. The aqueous layer was extracted with 3×25 ml of ethyl acetate and the combined organic layers were dried (MgSO4), and concentrated in vacuo to give a solid, mp=131°-133° C.
Reaction SMILES: [K+].[K+].S([O-])([O-])(=O)=O.O[C:9]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[CH:11]([CH3:15])[C:12]([OH:14])=[O:13].[OH-].[K+]>[Ni].O>[O:20]([C:19]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1O
Agent: [Ni]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Reaction time: 0.21 h
Yield: 97 %

Procedure:
To a solution of 4.2 g. of 2-hydroxy-3-phenoxy-hydratropic acid sulphate dipotassium salt in 50 ml. of water 2 g. of potassium hydroxide and 2 g. of a Raney nickel catalyst prepared freshly according to Urashibara, and the reaction mixture is stirred at 60° C. for 10 to 15 minutes. The catalyst is filtered off and the filtrate is acidified with a 20% aqueous hydrochloric acid solution. The separated solution is extracted with chloroform and the chloroform solution is dried over sodium sulphate and evaporated. 2.35 g. (97%) of 3-phenoxy-hydratropic acid are obtained. Melting point of the corresponding cyclohexylamine salt: 151° C. to 153° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][C:22]1[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1.COC(=O)CC(=O)CCOC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:28]([C:27]2[C:22]([CH2:21][CH2:20][O:19][CH3:18])=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Agent: COCCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl-ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=426.04.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH:27]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH:20]3[CH2:25][CH2:24][N:23]([CH:27]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(Br)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(COCc1ccccc1)N1CCC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 36.7 %

Procedure:
A mixture of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)4-piperidinylcarbamate (1.087 g, 3.11 mmol) (for a synthesis see WO2004/058144 Example 99(h)), methyl 2-bromo-3-[(phenylmethyl)oxy]propanoate (1.0 g, 3.66 mmol) and potassium carbonate (0.860 g, 6.22 mmol) in DMF (50 ml) was heated to 80° C. and stirred under argon for 2.5 h. The solvents were removed under reduced pressure and the residue treated with saturated aqueous sodium bicarbonate. The aqueous was extracted with DCM (5×100 ml) dried MgSO4, filtered and concentrated under reduced pressure. The crude product was chromatographed, eluting with 0-100% EtOAc/40-60 petroleum ether. Appropriate fractions were combined and evaporated under reduced pressure. The residue was then dissolved in DCM (50 ml) and washed with water (20 ml). The organic layer was separated, dried MgSO4 and evaporated under reduced pressure to afford product (618 mg, 35% yield).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]#[CH:25]>CC(C)=O>[C:23]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)#[C:24][CH3:25]
Reactant: O=c1c2ccccc2oc2ccc(O)cc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
A mixture of 2-hydroxyxanthen-9-one (2.12 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.25 g of a product with the following characteristics: m.p.153-154° C.; 1H NMR (CDCl3) δ: 2.58 (m, 1H), 4.8 (s, 2H), 7.35-8.38 (m, 7H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc2[nH]ccc2c1
Yield: 86.7 %

Procedure:
A solution of 1H-indole-5-carbonitrile (3.7 g) in tetrahydrofuran (25 ml) was added over fifteen minutes to a stirred suspension of lithium aluminium hydride (3.1 g) in tetrahydrofuran (80 ml) under nitrogen. After thirty minutes, the suspension was heated at reflux for two hours. After cooling to 0°, water (3.1 ml), sodium hydroxide (2N, 6.2 ml) and water (9.3 ml) were added with caution, the resulting salts were filtered off and the filtrate was concentrated under vacuum to afford a yellow oil (3.3 g) which was crystallised from ethyl acetate to give the title compound as a pale cream solid m.p. 114°-5°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17](=[O:51])[C@@H:18]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:37])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1>>[NH2:16][C:17](=[O:51])[C@@H:18]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])=[O:37])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:6]=3[CH:15]=2)=[CH:22][CH:21]=1
Reactant: COCCn1c(=O)oc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21

Procedure:
The sub-title compound was prepared by the method of Example 96 step (a) using 5-bromo-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one and (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([Cl:10])[C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(C)c(Cl)c1O
Reaction time: 1 h

Procedure:
The product from Example 9, Stage 1a (4.8 g), was stirred in acetic acid (20 ml) and acetic anhydride (5 ml) was added in one portion. Stirring was continued for 1hour after the initially exothermic reaction had subsided. The product was isolated by filtration and recrystallised from aqueous ethanol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[N:12]=[N:13][C:14]([Cl:20])=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[Cl:20][C:14]1[N:13]=[N:12][C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (9.21 g, 38.86 mmol) and 3,6-Dichloro-pyridazine-4-carboxylic acid (10.84 g, 64.77 mmol) in THF (80 mL) at −78° C., was added LiHMDS (5 g, 25.91 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25% ethyl acetate-hexane) to give pure product. LC/MS [4.52 min; 394 (M+1)].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH:2]1[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1Cc2ccccc2O1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-2-carboxylic acid (500 mg, 3.1 mmol) in anhydrous dichloromethane (20 ml), under nitrogen, was added 1,1′-carbonyldiimidazole (543 mg, 3.4 mmol). After stirring for 1 h, N,O-dimethylhydroxylamine hydrochloride (327 mg, 3.4 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was washed with hydrochloric acid (1N), followed by 10% aqueous potassium carbonate solution, and the organic phase was separated, dried (MgSO4) and concentrated in vacuo to give the title compound (352 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CN.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: CNCc1cc2ccccc2n1C
Reactant: C=CC(=O)Cl
Agent: CN
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 0.75 h

Procedure:
To a solution of 1-methyl-2-(methylaminomethyl)indole (0.96 g, 5.5 mmole), from Preparation 1, and methylamine (1.54 mL, 11.0 mmole) in CH2Cl2 (50 mL) at 5° C. was added acryloyl chloride (0.48 mL, 6.0 mmole). After 45 min, the reaction solution was poured onto H2O and the layers were separated. The organic phase was dried over Na2SO4 and concentrated to afford the title compound as a yellow oil. This was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:36]([CH3:35])(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(C)(=O)=O)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, methanesulfonyl chloride.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][CH2:28][CH2:29][OH:30]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:30][CH2:29][CH2:28][F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCF
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCF)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2-fluoroethanol (113.8 μl; 1.84 mmol), example 61 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([O:24]CC)=[O:23])[CH:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([OH:24])=[O:23])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)O)c1C(=O)NCCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 1-methyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylate (76 mg, 214 μmol) in THF (0.9 mL) and ethanol (0.3 mL) was added LiOH (1M aqueous solution, 428 μL, 428 μmol) at 0-5° C. The mixture was stirred at RT for 2 h. HCl (1M aqueous solution, 0.43 mL, 0.43 mmol) was added and the precipitating product was filtered, washed with THF/water 4:1 and dried in vacuo to give the product as colorless solid (52 mg, 159 μmol, 74.3%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1)#[N:2].C(C1C=NC=C(CCC(C)C)C=1)#N>>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(C#N)cc(NS(C)(=O)=O)c1
Agent: CC(C)CCc1cncc(C#N)c1
Product: CC(C)c1cc(CN)cc(NS(C)(=O)=O)c1

Procedure:
N-(3-(aminomethyl)-5-isopropylphenyl)methanesulfonamide was synthesized from N-(3-cyano-5-(prop-1-en-2-yl)phenyl)methanesulfonamide following the general procedure as described above for the 3-cyano-5-isopentylpyridine.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:8]([O:10]CC)=[O:9])=[CH:6][N:7]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[S:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(CC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 2-ethylthiazole-5-carboxylate (400 mg, 2.159 mmol) in MeOH (10 mL) is added 1N NaOH (6 mL, 6 mmol) After stirring at room temperature for 18 hours, the crude is concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-ethylthiazole-5-carboxylic acid (282.4 mg). HPLC retention time=0.78 minutes (condition D); MS (m+3)=160.4; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.6 Hz, 3H) 3.07 (q, J=7.6 Hz, 2H) 5.08 (br. s., 1H) 8.20 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].CS(O[CH2:28][CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:28][CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
Under inert atmosphere, a solution of 6.9 g (0.025 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 25 mL of anhydrous DMF was added dropwise to a suspension containing 1.2 g (0.030 mol) of sodium hydride (60% in mineral oil) in 70 mL of anhydrous DMF. After stirring at room temperature for 1 hour, a solution of 6.2 g (0.03 mol) of 2-thiophen-3-yl-ethyl methansulfonate in 15 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature for 30 minutes and then heated at 60° for 3 hours. The crude mixture was poured into water and extracted with dichloromethane. After drying, the solvent was removed under reduced pressure and 10.3 g of a crude oil were obtained. The crude mixture was purified by flash chromatography over silica gel affording 8.3 g (86% of yield) of the expected product.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[NH2:25][C:26]([CH:33]([CH3:35])[CH3:34])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)CO>[CH:33]([C:26]1[NH:25][C:14]([CH:15]([CH3:17])[CH3:16])=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C=C(N)C(C)C
Reactant: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Solvent: CC(=O)O
Solvent: OCCO
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(c2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2.86 ml (50 mmol) of glacial acetic acid are added to 13.45 g (50 mmol) of the compound from Example 97 and 17.4 g (100 ml) of ethyl 3-amino-4-methyl-pent-2-enoate in 80 ml of ethylene glycol and the mixture is heated to reflux overnight. After cooling to room temperature, it is concentrated vacuo and the residue is dissolved in dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is taken up in ethyl acetate. After extracting using 10% strength hydrochloric acid, water and saturated sodium hydrogen carbonate solution, the organic phase is dried again and concentrated, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether)).