Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].[NH2:3][C@H:4]([C:6]1[N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:14](=[O:22])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:23])[N:7]=1)[CH3:5].[NH2:24][C:25]1[N:30]=[C:29]([NH2:31])[C:28]([C:32]#[N:33])=[C:27](Cl)[N:26]=1.[CH:35](N(C(C)C)CC)(C)C>CS(C)=O>[NH2:24][C:25]1[N:30]=[C:29]([NH2:31])[C:28]([C:32]#[N:33])=[C:27]([NH:3][C@H:4]([C:6]2[N:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:23])[N:7]=2)[CH2:5][CH3:35])[N:26]=1.[NH2:24][C:25]1[N:30]=[C:29]([NH2:31])[C:28]([C:32]#[N:33])=[C:27]([NH:3][C@H:4]([C:6]2[N:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:23])[N:7]=2)[CH3:5])[N:26]=1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1cccnc1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2cccc(Cl)c2c(=O)n1-c1cccnc1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2cccc(Cl)c2c(=O)n1-c1cccnc1
Temperature: 25 °C
Yield: 166 %

Procedure:
Potassium fluoride (138 mg, 2.38 mmol) was added to a solution of (S)-2-(1-aminoethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (400 mg, 1.33 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (237 mg, 1.4 mmol) in diisopropylethylamine (1.0 mL, 6.0 mmol) and DMSO (3 mL). The resultant mixture was heated to 90° C. for 14 hours. Then it was cooled to room temperature, filtered, and purified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to obtain the title compound of (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile as a solid (479 mg). 1H NMR (400 MHz, DMSO) δ 8.74 (d, J=2.4 Hz, 0.5H), 8.58 (dd, J=4.8, 1.5 Hz, 0.5H), 8.51 (dd, J=4.9, 1.7 Hz, 1.5H), 8.06 (dm, J=8.5 Hz, 0.5H), 7.85 (dm, J=8.0 Hz, 0.5H), 7.8 (td, J=8.1, 1.4 Hz, 1H), 7.68 (ddd, J=8.2, 3.9, 1.2 Hz, 1H), 7.60 (dt, J=7.9, 1.3 Hz, 1H), 7.55 (ddd, J=8.1, 4.8, 0.7 Hz, 0.5H), 7.48 (ddt, J=8.1, 4.8, 0.7 Hz, 0.5H), 4.85 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). ES/MS 434.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](ON2C(=O)CCC2=O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]2)=[O:28])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
N-Benzylpiperazine (40.0 ml) was added in one portion to a solution of succinimido 1-t-butoxycarbonylpiperidine-4-carboxylate (75.0 g) in dry dichloromethane (1600 ml). The solution was stirred at ambient temperature under an atmosphere of argon for 17 hours. The solution was washed with water (500 ml) and saturated brine (250 ml). The organic layer was dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on alumina, eluting with dichloromethane to give 1-benzyl-4-[(1-t-butoxycarbonyl-4-piperidyl)carbonyl]piperazine as an oil;
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)=[CH:10][CH:9]=2)[N:4]=1.Cl.[N:21]1([C:26](N)=[NH:27])C=CC=N1.C(N(CC)C(C)C)(C)C.C(O[C:41](=[O:51])[CH2:42][C:43](=O)[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][N:45]=1)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(O)C>[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][N:16]([C:26]4[NH:27][C:41](=[O:51])[CH:42]=[C:43]([C:44]5[CH:49]=[CH:48][N:47]=[CH:46][N:45]=5)[N:21]=4)[CH2:15]3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: N=C(N)n1cccn1
Reactant: Cc1nc(-c2ccc([C@H]3CNCCO3)cc2)no1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc([C@H]3CN(c4nc(-c5ccncn5)cc(=O)[nH]4)CCO3)cc2)no1
Yield: 32.7 %

Procedure:
To a solution of (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholine hydrochloride (intermediate 13, 4.00 g, 14.2 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (2.19 g, 14.9 mmol) in N,N-dimethylformamide (14 ml) was added. N,N-diisopropylethylamine (4.05 g, 31.3 mmol) at room temperature and the solution was stirred for 4 hours. The solution was decanted with ether, then 3-oxo-3-pyrimidin-4-yl-propionic acid ethyl ester (3.59 g, 18.5 mmol), potassium carbonate (4.92 g, 35.6 mmol) and ethanol (30 ml) were added to the resulting solution. After refluxed for 18 hours, the solution was concentrated under reduced pressure. The residue was washed with water and the hot mixture of ethanol and 1N hydrochloric acid (1/1, v/v), and dried under reduced pressure to afford 2-{(2S)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-morpholin-4-yl}-1H-[4,4′]bipyrimidinyl-6-one (1.94 g, 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:36])[CH:16]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH2Cl2 (200 mL) was added dropwise (triphenyl-λ5-phosphanylidene)-acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) at 0° C. After the addition was complete, the resulting mixture was stirred for 1 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.23 (dd, J=0.8, and 8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.36 (t, J=6.8 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:21]=1)[CH2:10][C:9]2([CH3:29])[CH3:28])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:28][C:9]1([CH3:29])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:21]=2)[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
A mixture of 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.40 g, 1.0 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.30 g, 81%) as a white solid which was used for next step without further purification: MS (ESI) M+1=368.2;
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: COc1ccc(CCC=O)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(OC)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (11.500 mmol) and 3-(3-fluoro-4-methoxy-phenyl)-propionaldehyde (2.514 g; 13.800 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.70 min.; [M+H]+=429.88 g/mol.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([C:24](OC)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-:28].[NH4+]>C(O)(=O)C>[CH2:10]([N:17]1[CH2:22][C:21](=[O:28])[C:20]2[N:1]=[C:2]3[N:3]=[C:4]([S:7][CH3:8])[NH:5][N:6]3[CH2:24][C:19]=2[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: [OH-]
Reactant: CSc1n[nH]c(N)n1
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CSC1=NC2=NC3=C(CN(Cc4ccccc4)CC3=O)CN2N1
Reaction time: 5.5 h
Yield: 54 %

Procedure:
A solution of 39.05 g (0.3 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole, 85.1 g (0.3 mole) of 1-benzyl-3-carbomethoxy-4-piperidone-hydrochloride and 125 ml of acetic acid is heated to boiling for 5.5 hours. The reaction mixture is cooled and 350 ml of concentrated ammonium hydroxide are added. The mixture is allowed to stand for 16 hours at room temperature, the precipitated crystals are filtered and washed with water. The product is heated to boiling in 300 ml of methanol for 15 minutes and filtered again. The product is dissolved in hot dimethyl formamide, precipitated by adding acetonitrile, filtered and washed with acetonitrile. Thus 53.6 g of 7-benzyl-2-methylthio-6,7,8,9-tetrahydro-pyrido[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained, yield 54%, m.p.: 245°-247° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16](O)CO>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1I
Temperature: 0 °C
Yield: 110.6 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (20.0 g, 58.4 mmol; Example 212, step 1) and 1,2-ethanediol (6.5 mL, 120 mmol) in toluene (190 mL) was treated with p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The flask was fitted with a Dean-Stark trap that was filled with sieves, and refluxed for 3 h. The reaction mixture was cooled and added to ice cooled saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-20%) to give the desired product (22 g, 99%). LCMS for C12H14ClFIO3 (M+H)+: m/z=387.0; Found: 386.9.
Reaction SMILES: Br[C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.Cl.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])(=O)C.[Na+]>CN(C=O)C>[CH3:9][S:8][C:5]1[N:6]=[CH:7][C:2]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]=3[NH:15][C:10](=[O:12])[C:3]=2[N:4]=1
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nc(SC)ncc12
Temperature: 120 °C
Yield: 79.6 %

Procedure:
In a microwave vessel, methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1.0 eq, 274 mg, 1.18 mmol), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (1.2 eq, 329 mg, 1.42 mmol), and sodium acetate (3.0 eq, 291 mg, 3.55 mmol) were mixed in anhydrous DMF (2 ml). The mixture was degassed by bubbling nitrogen gas in the solution for 10 min and the reaction heated under microwaves at 120° C. for 30 min. After cooling down the expected material crashed out of NMP. The solid was filtered, suspended in water filtered and dried. The material was triturated in AcOEt and filtered give a yellow solid. The same procedure was repeated 9 times using the same amounts of materials to provide methyl 3-(methylthio)-5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (283 mg, 10% yield). LCMS (ES): >95% pure, m/z 302 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 2.71 (s, 3H), 3.89 (s, 3H), 7.80 (dd, J=1.6, J=8.4, 1H), 7.97 (d, J=1.6, 1H), 8.59 (d, J=8.8, 1H), 9.98 (s, 1H), 12.34 (s, 1H) ppm.
Reaction SMILES: FC1C=C(CN)[CH:5]=[N:6]C=1.[NH:10]1[CH:14]=[CH:13][C:12](CN)=[N:11]1.[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]2=[O:38])[S:21][C:22]=1[C:23]([OH:25])=O>>[NH:11]1[CH:12]=[C:13]([CH2:5][NH:6][C:23]([C:22]2[S:21][C:20]([N:26]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]3=[O:38])=[N:19][C:18]=2[CH3:17])=[O:25])[CH:14]=[N:10]1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: NCc1cc[nH]n1
Reactant: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cn[nH]c1
Yield: 3 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (1H-pyrazol-3-yl)methanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 3% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.34-8.32 (m, 1H), 7.58-7.57 (m, 1H), 6.14 (s, 1H), 4.37 (d, J=5.5 Hz, 2H), 4.02-3.96 (m, 2H), 3.59-3.53 (m, 2H), 3.33-3.28 (m, 2H), 2.46 (s, 3H), 2.32-2.26 (m, 2H), 1.76-1.71 (m, 2H); MS (ES+) m/z 416.7 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([C:17](=[O:32])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C)C=O>[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C@@H:7]([C:17](=[O:32])[N:18]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)[C@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C)c1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
61 mg (2.54 mmol) of sodium hydride are added to the solution of 1 g (2.31 mmol) of tert-butyl (2R,4R)-4-methoxy-2-[4-(3-oxomorpholin-4-yl)-phenylcarbamoyl]pyrrolidine-1-carboxylate (prepared analogously to Example 7.1) in 20 ml of dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. 022 mg (2.31 mmol) of methyl bromoacetate is subsequently added to the reaction mixture, which is then left to stir at room temperature for 12 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of methylene chloride each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 1.1 g of tert-butyl (2R,4R)-4-methoxy-2-{methoxycarbonylmethyl-[4-(3-oxomorpholin-4-yl)phenyl]-carbamoyl}pyrrolidine-1-carboxylate as a yellow oil; ESI (M-BOC) 392.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])(=[O:18])[CH3:17]
Reactant: C#C[C@@H](O)CCCCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#C[C@H](CCCCC)OC(C)=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(S)-1-octyn-3-ol (100 g., 0.794 mole) is dissolved in pyridine (79 g., 1.0 mole) and acetic anhydride (81.6 g., 0.8 mole) is added dropwise with stirring during 1 hour. The temperature rises to 45° C. The solution is heated at 55° C. for 1 hour and then is cooled and poured into ice-cold 5% hydrochloric acid (200 ml.) providing a heterogeneous mixture which is extracted with ether. The organic extract is washed with water and saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. yields a residual oil which is distilled to give the title compound (106.4 g., 80%), b.p. 91°-92° C./15 mm.; [α]D26 -79° (C 3.0, CHCl3).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:36][CH2:35][C:12]2[N:13]=[C:14]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=5)[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.O>C1COCC1>[F:34][C:31]1[CH:32]=[C:33]2[C:28]([CH2:27][CH2:26][N:25]2[CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][C:14]3[S:15][C:11]4[CH2:10][CH:9]([OH:8])[CH2:36][CH2:35][C:12]=4[N:13]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2c(s1)CC(O)CC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4-(6-fluoroindolin-1-yl)piperidine-1-carboxamide (106 mg, 0.2 mmol) in THF (3 mL) was added TBAF solution (1.0 M in THF, 0.8 mL, 0.8 mmol, 4 equiv) at room temperature. The resulting mixture was stirred at room temperature for 24 h and was poured into EtOAc/H2O (20 mL/20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 70-90% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)piperidine-1-carboxamide as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:15][C:16]=1[C:17]([NH:19][NH2:20])=[O:18].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:30][CH:31]=2)=[N:15][C:16]=1[C:17]1[O:18][C:33](=[O:35])[NH:20][N:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
DIPEA (86.08 mg, 116.0 μL, 0.6660 mmol) was added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) in DCM (6.500 mL) under nitrogen. A solution of triphosgene (39.53 mg, 0.1332 mmol) in DCM (100.0 μL) was then added dropwise to the stirred solution. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the solid obtained dried under vacuum to yield the product (106. g mg, 98% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 7.33 (br s, 2H), 7.52 (d, 2H), 8.09 (d, 2H), 8.89 (s, 1H) and 12.98 (br s, 1H) ppm; MS (ES+) 327.12
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]3[CH:37]=[CH:36][NH:35][C:29]=3[N:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39]>CN1CCCC1=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]4[CH:37]=[CH:36][NH:35][C:29]=4[N:30]=[C:31]([C:33]#[N:34])[N:32]=3)=[CH:23][C:22]=2[C:38]([F:39])([F:40])[F:41])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCN)CC1
Reactant: N#Cc1nc(-c2ccc(F)c(C(F)(F)F)c2)c2cc[nH]c2n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CCNc2ccc(-c3nc(C#N)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
2-(1-Methylpiperidin-4-yl)ethanamine (93 mg) and N,N-diisopropylethylamine (0.22 mL) were added to a mixture of 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and N-methylpyrrolidone (2 mL), and the mixture was stirred at 140° C. for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, the reaction mixture was purified by silica gel column chromatography (CHCl3:MeOH=98:2 to 85:15), whereby 4-[4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (66 mg) was obtained as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH3:10][NH:11][C:12](=[N:15][C:16]#[N:17])SC>C(#N)C>[C:16]([NH:15][C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[N:11][CH3:10])#[N:17]
Reactant: CNC(=NC#N)SC
Reactant: c1nc2c([nH]1)CCNC2
Solvent: CC#N
Product: CN=C(NC#N)N1CCc2[nH]cnc2C1
Yield: 30.9 %

Procedure:
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.29 g of N,S-dimethyl-N'-cyano-isothiourea ##STR3## in 15 ml of acetonitrile is refluxed for 21 h. After evaporation to dryness, chromatography on silica gel (ethyl acetate-ethanol as eluant) of the residue gives 630 mg of the pure title compound, m.p. 240°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[N:18]12CCCN=C1C[CH2:22][CH2:21][CH2:20][CH2:19]2.BrCCCC#N.CN(C)C=O>O>[C:19]([CH2:20][CH2:21][CH2:22][O:16][C:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])#[N:18]
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCOC(=O)c1cc(-c2ccc(O)cc2)ccc1O
Temperature: 75 °C
Yield: 70.6 %

Procedure:
A mixture of 4,4′-dihydroxy-3-biphenylcarboxylic acid (2.3 g; 10 mmol), 1,8-diaza-bicyclo[5.4.0]undec-7-ene (1.7 g; 11.2 mmol), 4-bromobutyronitrile (1.7 g; 11.2 mmol) and N,N-dimethylformamide (40 ml) was heated at 75° C. for 4 h. The reaction mixture was cooled, poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (3.0 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (97:3) as eluent to give 2.1 g (70%) of 3-cyanopropyl-4,4′-dihydroxy-3-biphenylcarboxylate.