Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([O:14][CH2:15][CH3:16])=[CH:6][C:5]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C2CC2)cc1C(=O)OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccccc2)c(C2CC2)cc1C(=O)OC
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of methyl 5-cyclopropyl-2-ethoxy-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.5 g), phenylboronic acid (1.66 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.418 g), a 2 M aqueous sodium carbonate solution (10.2 mL), tris(dibenzylideneacetone)dipalladium(0) (0.435 g), and toluene (20 mL) was stirred overnight at 100° C. in an argon atmosphere. The reaction mixture was allowed to cool to room temperature. Then, the organic layer was separated and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.80 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.BrC1C=C2C(C=CN2)=CC=1.C([O-])([O-])=O.[K+].[K+].[C:40](=[O:47])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:41].CNC1CCCCC1NC>[Cu]I.C1(C)C=CC=CC=1>[C:43]([O:42][C:40](=[O:47])[NH:41][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(Br)cc3n2CC)cc1
Agent: [Cu]I
Agent: Brc1ccc2cc[nH]c2c1
Agent: CNC1CCCCC1NC
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2c(C#N)c3ccc(NC(=O)OC(C)(C)C)cc3n2CC)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole as described in example 1Gb, is mixed with K2CO3 (0.55 g, 4.0 mmol), CuI (0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol), N,N′-dimethylcyclohexane-1,2-diamine ligand (0.028 g, 0.2 mmol) and anhydrous toluene (5.0 mL) in a sealed tube. The reaction system is flushed with nitrogen and then stirred at 110° C. overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, dichloromethane) to provide [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (0.68 g, 84%), compound 832.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[S:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[C:7]1=[O:32])=[O:5])[CH3:2].O=S(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:32])=[C:8]2[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:24][S:23][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2c(-c3ccccc3)nsc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution of 6-(2,4-dimethoxy-benzyl)-4-oxo-3-phenyl-4,5,6,7-tetrahydro-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (5.42 g, 11.99 mmol) in CH2Cl2 was added SOCl2 (1.31 mL, 17.98 mmol) and the mixture was stirred at r.t. After 3 h the mixture was filtered and the filter cake was washed with hexanes/CH2Cl2 (4/1, 12 mL). The solid was then suspended in sat. NaHCO3 (200 mL) and the mixture extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, water, dried over MgSO4, and concentrated in vacuo to give the title compound as yellow solid (2.56 g): MS (m/z) 301.1 (M+1).
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[N:49][CH:50]=2)=[C:38]([O:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[N:49][CH:50]=2)=[C:38]([O:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:37]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cn3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 396 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 395.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:23][N:24]([CH3:32])[CH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>C1COCC1>[CH3:23][N:24]([CH3:32])[CH:25]1[CH2:30][CH2:29][CH:28]([O:31][C:2]2[C:3]3[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Reactant: CN(C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (100 mg, 0.32 mmol, 1.00 equiv) in freshly distilled THF (20 mL) was added sodium hydride (64 mg, 1.6 mmol, 5.0 equiv, 60% dispersion in mineral oil) at 0° C. under nitrogen. After stirring for 30 min at room temperature, a solution of 4-(dimethylamino)cyclohexan-1-ol (50 mg, 0.35 mmol, 1.06 equiv) was added and stirred overnight at room temperature. The reaction was then quenched by the addition of brine and extracted with EtOAc. The organic layers was combined and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was applied onto a silica gel column with DCM/MeOH (50:1-30:1) to provide 70 mg (52%) of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a light yellow solid. MS (ES): m/z 421 (M+H)+.
Reaction SMILES: [Na].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26]>C(O)C>[C:28]([CH2:29][N:22]1[N:23]=[N:24][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH:15]=2)=[N:21]1)([O:27][CH2:25][CH3:26])=[O:31]
Reactant: c1cc(OCc2ccc3ccccc3n2)cc(-c2nnn[nH]2)c1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1nnc(-c2cccc(OCc3ccc4ccccc4n3)c2)n1
Reaction time: 16 h

Procedure:
To a solution of 0.2 g sodium in 30 ml ethanol was first added 1.1 g of 5-[3-(2-quinolylmethyloxy)phenyl]tetrazole and then 30 minutes 0.6 g of ethylbromoacetate and stirring was continued at 80° C. for 16 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].C(O)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.[C-]#N.[K+]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:2]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(CC(=O)OCc2ccccc2)CCCCC1
Yield: 68 %

Procedure:
401 mg (2 mmol) of (1-cyanocyclohexyl)acetic acid ethyl ester, 1.09 g (10 mmol) of benzyl alcohol and 6 mg (0.1 mmol) of potassium cyanide were refluxed for 24 hours in 5 ml of toluene. Then the solution was washed with 25 ml of water, freed of solvent and distilled in high vacuum. 350 mg of (1-cyanocyclohexyl)acetic acid benzyl ester was obtained, corresponding to a yield of 68 percent (relative to the (1-cyanocyclohexyl)acetic acid ethyl ester used). Data for the product was:
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12]>Cl>[ClH:1].[CH2:9]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCO
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: CCCCOC(=O)[C@@H](N)CS
Yield: 30 %

Procedure:
L-Cysteine hydrochloride (100 g) was dissolved in 250 ml of butanol saturated with dry HCl. The solution was heated under reflux for 4 hours. Excess of solvent was evaporated under evaporator. Ethyl acetate (150 ml) was added to the residue to give crystals. The crystals were recrystallized from ethyl acetate, mp 91° C., yield 30%, IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ9.2-8.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH), 4.3 (t, 2-, --CH2)--,, 3.3 (b, 2, CH2S), 1.0 (t, 3, --CH3 --), 1.0-3.0 (m, 4, --CH2CH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=3[F:25])[N:3]=2)=[C:10]([F:17])[CH:11]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Fc1cc(Br)cc(F)c1Cc1cccc(Br)n1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cccc(Cc3c(F)cc(Br)cc3F)n2)c(F)c1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-6-(4-bromo-2,6-difluorobenzyl)pyridine (from Step C above, 7.41 g, 20.53 mmol) in toluene (200 mL) was added (2,4-difluorophenyl)boronic acid (3.89 g, 24.63 mmol), tetrakis(triphenylphosphine)palladium (2.37 g, 2.05 mmol), ethanol (20 mL) and 2M Na2CO3 (20 mL). The reaction was heated to 90° C. until complete. The mixture was cooled to room temperature and concentrated. The crude residue was diluted with EtOAc/water (1:1) and washed with 1N HCl (2×), brine (3×), dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (7.23 g).
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]3([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[CH2:48][C:47]1=[O:57])[CH2:35][O:36]2>>[CH2:1]([N:41]([CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:48][C:47]1=[O:57])[CH:34]1[CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[CH:40][C:31]=2[O:30][CH3:29])[O:36][CH2:35]1)[CH2:2][CH3:27]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1
Yield: 72 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 9, the expected product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](C(OC)=O)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (4.00 g, 13.0 mmol) was taken up in THF (30 mL) and MeOH (10 mL) under N2. NaOH (2 M, 19.5 mL, 39.0 mmol) was added, and the reaction was stirred at room temperature for 45 min. The solution was quenched with 1 M citric acid and extracted with EtOAc (2×). The combined organic extracts were washed with water and brine, dried (MgSO4), and evaporated. The resulting yellow oil was dissolved in 1:1 EtOAc:water (100 mL) and stirred at 85° C. for 2 h. The mixture was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated to give [4-(tert-Butoxycarbonyl)phenyl]acetic acid as a tan solid. 1H NMR (DMSO-d6, 600 MHz) δ 12.42 (bs, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 3.64 (s, 2H), 1.51 (s, 9H). MS: cal'd 259 (MNa+), exp 259 (MNa+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.[OH-].[Na+].O>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:6]2/[C:7](=[O:11])[C:8]3[C:4]([CH2:5]/2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[CH:13]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Cc2cc(O)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A solution of 5-hydroxy-2,3-dihydro-1H-inden-1-one (0.30 g, 2.0 mmol) and 1H-indole-3-carboxaldehyde (0.32 g, 2.2 mmol) in methanol (10 mL) was added with 50% sodium hydroxide (0.34 mL), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with water, and the precipitated solid was collected by filtration, and washed with methanol to obtain (E)-2-[(1H-indol-3-yl)methylene]-5-hydroxy-2,3-dihydro-1H-inden-1-one (0.45 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:26]([C:23]2[CH:24]=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)CNc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of (4-fluoro-phenyl)-isobutyl-amine (250 mg, 1.5 mmol) in DCM (5 mL) was added pyridine (242 μL, 3.0 mmol) followed by 6-chloropyridine-3-sulfonyl chloride (379 mg, 1.8 mmol) and the reaction was stirred at room temperature for 2 hours. Water and saturated aqueous NaHCO3 were added and then extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (411 mg, 67%). LCMS (m/z, Method A) ES+ 343 [M+1]+.
Reaction SMILES: C([O-])=O.[NH4+].[Na+].O=[C:7]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])[C:8]([O-:10])=[O:9].N.C1[N:18]=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.N[C@H](C(O)=O)CC(C)C.C([O-])=O.C>O>[CH3:14][C:11]([CH2:12][CH3:13])([CH3:15])[C@@H:7]([C:8]([OH:10])=[O:9])[NH2:18]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: CCC(C)(C)C(=O)C(=O)[O-]
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N
Agent: O=C[O-]
Solvent: O
Product: CCC(C)(C)[C@H](N)C(=O)O

Procedure:
6.3 g (0.1 mole) ammonium formate and 1.67 g (10 mmoles), 2-keto-3,3-dimethyl pentanoic acid sodium salt are suspended in 80 ml of water, the pH value is adjusted with ammonia to 8.2, so that the solids dissolve and the volume is adjusted to 100 ml. subsequently, 14.34 mg (0.02 mmole) NAD+3H2O cofactor as well as 800 U of leucine dehydrogenase (LeUDH) and 500 U of rec-formate dehydrogenase (rec-FDH) are added. The temperature is set to 32° C . During the reaction the system is gently stirred and the pH value is adjusted to 8.2 via a pH stat unit. The completion point of the reaction is sdemonstrated by determining the degree of conversion with HPLC. The reaction solution is adjusted to pH 9,5 with ammonia and subsequently clarified with 2% active charcoal. The almost colourless solution is concentrated with a rotary evaporator, the amino acid is crystallized, is separated via a filter funnel, washed three times with a little ethanol and dried overnight under vacuum at 50° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][C:7]=1[CH:15]=[O:16].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:7]=1[CH:15]=[O:16]
Reactant: CN(C)CCOc1ccc(B(O)O)cc1C=O
Reactant: Brc1cccnc1
Product: CN(C)CCOc1ccc(-c2cccnc2)cc1C=O
Yield: 13 %

Procedure:
General procedure G using 4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and 3-bromo-pyridine gave the title product as yellow oil in 13% yield. 1H-NMR (CDCl3) δ 10.46 (s, 1H), 8.76 (d, 1H), 8.52 (dd, 1H), 8.00 (d, 1H), 7.80 (dt, 1H), 7.72 (dd, 1H), 7.30 (ddd, 1H), 7.07 (d, 1H), 4.28 (t, 2H), 2.90 (t, 2H), 2.42 (s, 6H).
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)=O)C.C[Mg]Br>C1COCC1>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:14]([OH:24])([CH3:15])[CH3:13])[N:7]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: CCOC(=O)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(C(C)(C)O)cs2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-4-carboxylic acid ethyl ester (20 mg, 0.056 mmol) in dry THF (2 ml) at 0° C. was added methylmagnesium bromide (3M solution in THF, 93 μl, 0.279 mmol) added and stirred at 0° C. for 2 h. The reaction mixture was cautiously quenched with saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with diethyl ether, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a light brown oil (14.4 mg, 75%). MS ISP (m/e): 345.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].B(F)(F)F.[CH3:26][CH2:27]OCC.O>C(O)C>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([O:16][CH2:26][CH3:27])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCOCC
Reactant: CCCC1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: FB(F)F
Solvent: O
Solvent: CCO
Product: CCCC1Cc2c(c(C)c(C)c3oc(C(=O)OCC)cc23)C1=O

Procedure:
To a solution of 4,5-dimethyl-6-oxo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (8.0 g.) in ethanol (50 ml.) is added borontrifluoride etherate (13 ml.). The reaction mixture is refluxed for 0.5 hour, treated with water and cooled to afford ethyl [4,5-dimethyl-6-oxo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]-furan-2-carboxylate] after filtration and drying.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C1COCC1>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[C:3]2[CH:10]=[CH:9]1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1ccnc2[nH]ccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.944 g, 4.79 mmol) in THF (10 ml) was added dropwise to sodium hydride (0.240 g, 5.99 mmol) in THF (10 ml) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 10 minutes. The reaction mixture was cooled to −78° C. and n-butyllithium in hexanes (2.396 mL, 5.99 mmol) was added dropwise over 10 minutes and stirred at −78° C. for 10 minutes. Triisopropyl borate (3.32 mL, 14.37 mmol) was added dropwise over 2 minutes and the reaction mixture allowed to warm to RT over 1.5 hours. The reaction mixture was quenched with water (10 ml) and C18 silica gel was added (10 g) and the mixture was concentrated in vacuo. The resultant solid was purified by reverse phase flash silica chromatography, eluting with a gradient of 5 to 40% acetonitrile in water. Pure fractions were evaporated to afford 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (0.590 g, 76%); m/z: (ES+) MH+, 162.88.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:23](OC)=[O:24])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][OH:24])=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)n(C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(CO)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon 14.7 g of methyl 2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indole-7-carboxylate are dissolved in 120 ml of tetrahydrofuran, cooled to 0° C. and combined dropwise with 60 ml of a 1 M solution of lithium aluminium hydride in tetrahydrofuran. The mixture is stirred for 2 hours and then the reaction is stopped by the dropwise addition of 30 ml of 2 N sodium hydroxide solution. Then the mixture is stirred for 30 minutes, diluted with ethyl acetate and filtered through kieselguhr. The filter cake is taken up in 60 ml of tetrahydrofuran, stirred for 10 minutes and suction filtered through kieselguhr again. The combined organic phases are dried on magnesium sulphate and evaporated down in vacuo. The residue is extracted from methanol. The precipitated solid is filtered off and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:12]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)#[N:13]
Reactant: Clc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cn1
Yield: 53 %

Procedure:
A mixture of 2,5-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol), zinc (dust, 29 mg, 0.45 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (0.18 g, 0.22 mmol) in N,N-dimethylformamide (10 mL) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 735 mg (53%) of 2-cyano-5-chloropyridine.