Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](=O)([O-:13])N.[BH4-].[Na+]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:13])[CH:2]=1
Reactant: NC(=O)[O-]
Reactant: c1ccc2ncccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cnc2ccccc2c1

Procedure:
Synthesis of compounds ERW1041A, B, C, D, E, and 1069 were synthesized using the methods of Choi et al. Chemistry & Biology, Volume 12, Issue 4, Pages 469-475, except the amino-acid amines are protected by a quinoline-containing carbamate. This quinoline-containing carbamate is synthesized by reducing 3-quinolylcarbaldehyde with sodium borohydride in THF followed by an aqueous workup and flash chromatography yielding 3-quinolylcarbinol. para-Nitro-phenylchloroformate is reacted with 3-quinolylcarbinol in methylene chloride and N-methyl morpholine to give a carbonate of 3-quinoline methanol and para-Nitro-phenol. After purification by flash chromatography, this carbonate is reacted with the methyl ester of the amino acid in neat DMF to give the named compounds.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 26 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 68 mg (70% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH:12]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(N)c(Cl)cc1CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(Cl)cc1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (50 mg, 0.240 mmol, Example 566A) in THF (0.5 mL) at room temperature was added morpholine (37.6 mg, 0.431 mmol), sodium cyanoborohydride (30.1 mg, 0.479 mmol), and a drop of acetic acid. The reaction was stirred at room temperature for 1 h at which point LCMS indicated full conversion. The reaction was quenched with aq. Na2CO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (0-10% MeOH/DCM) to give 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (54 mg) as yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19](=[O:26])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:14])([CH3:13])[CH3:12].C(O)(C)C>CCOC(C)=O>[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:19]([N:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:25]1)=[O:26])([CH3:14])([CH3:13])[CH3:12]
Reactant: Fc1ccc2nccn2n1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc3nccn3n2)CC1
Yield: 78 %

Procedure:
To 305 mg (2.23 mmol) of 6-fluoroimidazo[1,2-b]pyridazine, was added 1.00 g (3.34 mmol) of (S)-tert-butyl(4-methyl-1-oxo-1-(piperazin-1-yl)pentan-2-yl)carbamate, 10 mL of isopropyl alcohol, and 0.93 mL (6.68 mmol) of TEA. This was microwaved at 150° C. for 0.5 hr. It was diluted with EtOAc, washed with brine, and the organic layer was dried over MgSO4, and then concentrated. It was purified on the ISCO with a 40 gram column eluting with 0-10% MeOH/DCM to obtain the desired product in 78% yield.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[K+].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:30]([CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [H-]
Agent: [K+]
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)Cc1ccccc1

Procedure:
Starting from 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,3-dimethyl-2H-indol-2-one (Example 3), this compound was synthesised according to the method described for Example 23 using only one equivalent of potassium hydride and phenylacetyl chloride instead of isonicotinoyl chloride. If an excess of potassium hydride is used in this reaction (2 equivalents) a by-product (described in Example 28) is obtained as the major fraction.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C-:10]#[N:11].[K+].CS(C)=O>O>[C:10](#[N:11])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [C-]#N
Reactant: CCCCCC#CCBr
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC#CCC#N

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>O.C([BH3-])#N.[Na+].C(O)(=O)C>[CH2:15]([NH:22][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CC(=O)CCC2
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (3.6 g), benzylamine (2.5 ml), and acetic acid (27 ml) in water bath was added portionwise sodium cyanoborohydride (0.49 g), and the mixture was stirred at ambient temperature for 5 hours. Additional benzylamine (2.5 ml) and sodium cyanoborohydride (0.10 g) were added to the mixture, and stirring was continued for an additional 2 hours. The reaction mixture was made alkaline (pH>8) with 10% sodium hydroxide (150 ml), and extracted once with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; n-hexane-ethyl acetate; 3:1 to 2:1 to 1:1) to give N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (4.8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:17][CH3:16])=[O:11])[CH2:7]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 35.1 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1 -azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40 % aqueous monomethylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the solid which formed was collected by filtration (6.0 g). Recrystallization from benzene yielded 2.0 g (35.1%) of tan crystals, m.p. 134°-135° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH3:25])[C:11]3=2)[NH:6][CH:5]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][NH:14][CH:13]([CH3:25])[C:11]3=2)[N:6]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.010 g, 0.42 mmol) was added to tert-butyl 10-chloro-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 43, 18 mg, 0.050 mmol) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol) in DMF (2 mL). The mixture was was stirred at room temperature for 30 minutes. TFA (0.50 mL) was added to the reaction mixture and the solvent was evaporated. The residue was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (16.8 mg) in the form of the trifluoroacetate salt. MS m/z 377 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH2:15][CH2:16][CH3:17])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH2:15][CH2:16][CH3:17])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCC(=O)NC(C#N)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}butanamide (1.60 g, 6.5 mmol), triphenylphosphine (4.3 g, 16.3 mmol), and carbon tetrachloride (1.6 mL, 16.3 mmol) in acetonitrile (65 mL) was heated at 42° C. for 12 h. The reaction was then concentrated and the residue was stirred in CH2Cl2 (70 mL) and 0.5 N NaOH (60 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-40% EtOAc:hexanes) to give the title compound as a light yellow solid, in assumed quantitative yield due to inseparable triphenylphosphine oxide. 1H NMR (400 MHz, CDCl3) δ 7.30-7.40 (m, 5H), 4.52 (s, 4H), 2.58-2.68 (m, 2H), 1.68-1.82 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[CH2:36][CH3:37]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:34]=[C:35]([CH2:36][CH3:37])[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.56 g), anhydrous potassium carbonate (0.72 g), 1-bromobutan-2-one (0.785 g) and methanol (30 ml) was stirred at room temperature for 2.5 hours. To the mixture was added anhydrous potassium carbonate (0.72 g), and the mixture was stirred at room temperature 1.5 hours and refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-ethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.492 g) as oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C1[CH2:27][O:26][CH2:25]C1>>[CH3:25][O:26][CH:27]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1ccc2c(c1)CCC2=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC=C1CCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of CH3OCH2PPh3I (8.9 g, 26 mmol) in THF (80 mL) was added a solution of NaHMDS in THF (2.0M, 13 mL, 26 mmol)) at 0° C. The mixture was stirred 1 hour at 0° C. Then a solution of 1-Oxoindane-5-carbonitrile (2.0 g, 13 mmol) in THF (10 mL) was added. The mixture was stirred for 2 hours at 0° C. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatograph to give the title compound. MS m/z: 186 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[CH2:27][NH2:28])[C:6]([NH:8][C@H:9]([B:21]([OH:23])O)[CH2:10][C:11]1[C:12]([OH:20])=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:7].Br[C:30]#[N:31]>CN(C=O)C>[NH2:31][C:30]1[NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:6]([NH:8][C@H:9]3[CH2:10][C:11]4[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=4[O:20][B:21]3[OH:23])=[O:7])[CH:24]=[CH:25][C:26]=2[CH2:27][N:28]=1
Reactant: NCc1ccc(C(=O)N[C@@H](Cc2cccc(C(=O)O)c2O)B(O)O)cc1CN
Reactant: N#CBr
Solvent: CN(C)C=O
Product: NC1=NCc2ccc(C(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)cc2CN1
Reaction time: 5 h

Procedure:
To (R)-3-(2-(3,4-bis(aminomethyl)benzamido)-2-boronoethyl)-2-hydroxybenzoic acid (10 mg) in DMF (1 mL) was added BrCN (10 mg) and the reaction was stirred for 5 hr. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 395 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Reactant: NCCN
Product: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(NCCN)c3cc(Cl)ccc3n1)C2
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The mixture of 2-(4,6-dichloroquinolin-2-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide (133 mg, 0.32 mmol) and ethane-1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180° C. under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 11 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 438. 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.60 (d, J=8.0 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.38 (m, 1 H), 7.22 (m, 2 H), 6.01 (s, 1 H), 4.80 (s, 2 H), 4.16 (m, 2 H), 3.44 (t, J=6.4 Hz, 2 H), 3.11-2.97 (m, 10 H), 1.93 (m, 2 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCSCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and methyl thioglycolate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:22][C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH2:22][C:23]([CH3:24])=[O:25])[CH2:18][CH2:19]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
A mixture of 6-chloro-2-oxo-1-(1-piperazinyl)carbonylmethyl-1,2-dihydrothiazolo[5,4-b]pyridine (0.80 g), chloroacetone (0.24 g), and potassium carbonate (0.35 g) in dry N,N-dimethylformamide (2.4 ml) was heated at 80° C. for 30 min. The mixture was poured into an ice-water, and the precipitates obtained were extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and evaporated to give crude crystals (0.85 g). The crude crystals were recrystallized from a mixture of chloroform and ethyl acetate to give 6-chloro-2-oxo-1-[(4-acetonyl-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]3C=CC=[C:20](C)[C:19]=3S(OCCC)(=O)=O)[S:17][C:13]=2[N:12]2[C:32]([CH3:35])=[N:33][N:34]=[C:11]2[CH2:10][N:9]=1.[I-:36].[Na+]>CC(C)=O>[I:36][CH2:20][CH2:19][CH2:18][C:16]1[S:17][C:13]2[N:12]3[C:32]([CH3:35])=[N:33][N:34]=[C:11]3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: [I-]
Reactant: CCCOS(=O)(=O)c1c(C)cccc1-c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nnc2n1-c1sc(CCCI)cc1C(c1ccccc1Cl)=NC2
Yield: 36 %

Procedure:
0.6 g (0.0011 mol) of propyl 3-[4-(2-chlorophenyl)-9methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepin-2-yl]-toluenesulphonate, prepared analogously to Example 6, and a solution of 0.2 g (0.0014 mol) of anhydrous sodium iodide in 15 ml of anhydrous acetone are stirred for 2 hours at ambient temperature. After the solvent has been removed, the residue is taken up in methylene chloride/water, the organic phase is washed several times with water, then dried, the solvent is removed and in this way 0.2 g (yield 36% of theory) of the amorphous title compound are obtained.
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:10])[CH2:5][C:4]1([CH3:9])[C:6](Cl)=[O:7]>O1CCOCC1>[F:2][C:3]1([F:10])[CH2:5][C:4]1([C:6]([NH2:1])=[O:7])[CH3:9]
Reactant: N
Reactant: CC1(C(=O)Cl)CC1(F)F
Solvent: C1COCCO1
Product: CC1(C(N)=O)CC1(F)F
Yield: 81 %

Procedure:
Gaseous ammonia is passed for 90 minutes into a stirred solution of 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropane-carbonyl chloride in 80 ml of dioxane at 20° to 30° C. The resultant suspension is then evaporated to dryness under a waterpump vacuum. The residue remaining is stirred with 50 ml of water, filtered off with suction and dried. In this manner, 11 g (81% of theory) of 2,2-difluoro-1-methyl-cyclopropyl-carboxamide in form of a solid substance of melting point 125°-127° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:17][CH:18]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:19])=[C:8](\[C:15]#[N:16])/[C:9]([O:11]CC=C)=[O:10].N1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.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:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:17][CH:18]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:19])=[C:8](\[C:15]#[N:16])/[C:9]([OH:11])=[O:10]
Reactant: C=CCOC(=O)/C(C#N)=C(\NC(C)c1nccs1)c1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(N/C(=C(/C#N)C(=O)O)c1sccc1Br)c1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Allyl (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylate (0.1 g, 0.212 mmol, 1 eq.) was dissolved in 5 ml of DCM under Argon and cooled to 0° C. Pyrrolidine (0.018 g, 0.255 mmol, 1.2 eq.) added followed by triphenylphosphine (0.010 g, 0.038 mmol, 0.18 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.011 mmol, 0.05 eq.). The reaction was stirred at 0° C. for 2 h at which point no starting material remained. The reaction medium was quenched with aqueous HCl 1N (5 ml) and diluted with water. The organic layer was basified with aqueous 1N NaOH until pH 9 and was extracted again with aqueous 1N NaOH. The aqueous layers were combined, acidified with aqueous 1N HCl and extracted with DCM (CH2Cl2). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to give (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylic acid (0.075 g, 87% yield) as a white solid and a mixture of atropoisomers.