Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:19]=[CH:18][C:17]([C@@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3ccc(C(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(2S,4R)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (591 mg, 1.60 mmol) (from example 33, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 12 mL, 68.52 mmol) and the mixture stirred at room temperature. After 24 h more hydrogen bromide (33% in acetic acid, 5 mL, 28.55 mmol) was added and the reaction continued at room temperature for a total of 1.5 days. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (337 mg, 67%). 1H NMR (600 MHz, cd3od) δ 1.69-1.78 (m, 2H), 2.09 (d, 1H), 2.21 (d, 1H), 2.99-3.09 (m, 2H), 3.32-3.38 (m, 1H), 4.01-4.04 (m, 1H), 5.63 (s, 1H), 7.59 (d, 2H), 7.66 (d, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1156
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)(Cl)[CH2:10][N+:11]([O-:13])=[O:12]>CO>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: NCCCS
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Into 50 ml of methanol was added 8.1 g of 1-amino-3-propanethiol, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, about 1/3-aliquot of a solution of 5.0 g of caustic soda dissolved in 40 ml of methanol was added dropwise thereinto, and the remainder of about 2/3-aliquot of the solution and a solution of 5.4 g of 2,2,2-trichloro-1-nitroethane diluted in 20 ml of methanol were added dropwise slowly over 50 minutes, and the reaction was carried out for one hour. During the dropwise addition, the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction carried out for one hour, the procedure of the post-treatments as described in Example 1 was followed to obtain 4.20 g of tetrahydro-2-(nitromethylene)-1,3thiazine (yield: 86.8%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1.[C:20]1([CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]#[C:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:41][CH:40]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[OH:1][CH:2]([C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1)[CH2:3][N:27]([CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]#[C:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:43][CH:44]=1
Reactant: c1ccc(C2OCc3nc(C4CO4)ccc3O2)cc1
Reactant: CCCCC(=O)NCc1ccc(C#CCCOCCCCCCNCc2ccccc2)cc1
Solvent: CO
Product: CCCCC(=O)NCc1ccc(C#CCCOCCCCCCN(Cc2ccccc2)CC(O)c2ccc3c(n2)COC(c2ccccc2)O3)cc1
Yield: 52 %

Procedure:
A solution of 6-oxiranyl-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine (0.712 g) and N-[[4-[4-[[6-[(phenylmethyl)amino]hexyl]oxy]-1-butynyl]phenyl]methyl]pentanamide (1.25 g) in methanol (10 ml) was refluxed for 1l h. The methanol was evaporated to leave an oil which was purified by FCC eluting with ER to give the title compound as a yellow oil (1.02 g), t.l.c. ER:triethylamine (100:1) Rf 0.2
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([C:7]([NH2:9])=[O:8])[O:4][N:3]=1.[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:15][CH2:16][N:17]([C:2]2[CH2:6][CH:5]([C:7]([NH2:9])=[O:8])[O:4][N:3]=2)[CH2:18][CH2:19]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: NC(=O)C1CC(Br)=NO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CC(N2CCC(Oc3cc(F)ccc3Br)CC2)=NO1
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxamide (1.5 g, 7.77 mmol), 4-(2-bromo-5-fluorophenoxy)piperidine (2.56 g, 9.33 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.04 mmol) in ethanol (15 mL) was heated at reflux temperature overnight. Solvent was then removed in vacuo. The residue was suspended in water and stirred for 1 h. The solid was collected, washed with water and Et2O. Drying under vacuum gave the title compound as a light brown powder.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CS(C)=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CS(C)=O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of dimethyl sulfoxide. The stirred mixture is heated to 140° C. and held for 1.5 hours; then cooled to about room temperature. Then 150 ml 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 12.6 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 72.3% pure or a 58.8% yield.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1
Reactant: COCCOc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-(2-methoxyethoxy)phenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.39 (3H, s), 3.74 (2H, t, J=4.8 Hz), 4.18 (2H, t, J=4.8 Hz), 5.26 (2H, s), 5.81 (1H, s), 6.92 (1H, d, J=1.6 Hz), 6.98 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=5.2 Hz), 7.57 (1H, d, J=1.2 Hz), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H17ClN4O3, 385; Found, 385.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]#[N:29].N1CCOCC1>CN(C=O)C.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: N#CCCl
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: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.707 mmol) and Cs2CO3 (254 mg, 0.778 mmol) in anhydrous DMF (5 ml) was added chloroacetonitrile (0.054 ml, 0.85 mmol). The mixture was heated at 50° C. for 18 hours then allowed to cool to rt and degassed under a gentle vacuum then nitrogen introduced. This was repeated twice. Pd(PPh3)4 (82 mg, 0.071 mmol) was added and the mixture degassed once more, before morpholine (0.617 ml, 7.07 mmol) was added and the mixture left to stir for 3 hours at rt. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5-10% AcOH/MeOH. The product fraction was concentrated giving the title compound 52 mg (26%); NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J=7.5 Hz), 4.87 (s, 2H), 14.72 (br s, 1H); m/z 299.2 [MNH4+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[CH3:23][O:22][CH2:21][CH2:20][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:38]4[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[CH3:19]
Reactant: COCCN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COCCN(C)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 290. NMR (CDCl3): 1.63-1.70 (m, 2H, CH2), 1.78 (m, 2H, CH2), 2.09-2.15 (m, 2H, CH2), 2.36 (s, 3H, CH3), 2.50 (m, H, CH), 2.69 (m, 2H, CH2), 3.04-3.06 (m, 2H, CH2), 3.38 (s, 3H, CH3), 3.49 (m, 2H, CH2), 3.82 (s, 2H, CH2), 389-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.23 (s, 2H, NH2), 7.27 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=499.29
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[CH3:23]
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.82 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.43 g of sodium hydride (50% in oil), 100 ml of dimethylformamide and 0.7 ml of ethyl iodide were reacted as described in Example 9, giving 1.20 g of the desired product as tan crystals mp 122°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]SNC1C=CC=CC=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(OCC)(=O)C.CCCCCC>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:19]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C#CC(=O)OCC
Reactant: Nc1ccccc1SSNc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CNc2ccccc2S1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
2-(2-Aminophenyl)disulfanylaniline (1.0 g, 4.0 mmol) and ethyl prop-2-ynoate (790 mg, 816 μL, 8.05 mmol) were combined in a microwave tube and heated at 150° C. for 30 min. The reaction was concentrated in vacuo. Silcia gel chromatography (10-35% ethyl acetate/hexane) provided ethyl 4H-1,4-benzothiazine-2-carboxylate as an orange solid (200 mg, 23% yield). LC/MS m/z 222.0 [M+H]+. 1H NMR (400.0 MHz, CDCl3) δ 7.11 (d, J=6.6 Hz, 1H), 6.86-6.82 (m, 1H), 6.79-6.74 (m, 2H), 6.27 (d, J=7.9 Hz, 1H), 5.68 (br d, J=4.2 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added Et3N (240 mg, 2.4 mmol) and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0° C. The reaction solution was stirred at rt for 1 h. The reaction was quenched with H2O and the mixture was extracted with CH2Cl2. The organic phase was concentrated to give 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 98%), which was used for the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]1[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[N:8]1)=[O:6])([CH3:3])[CH3:2].[OH-].[K+].[CH3:24]I>ClCCl>[CH:1]([O:4][C:5]([C@@:7]1([CH3:24])[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccc(C2=NC(C(=O)OC(C)C)CS2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C2=N[C@@](C)(C(=O)OC(C)C)CS2)c(OC)c1

Procedure:
Isopropyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-carboxylate is reacted with 50% potassium hydroxide and excess methyl iodide in dichloromethane in the presence of O(9)-allyl-N-9-anthracenylmethylcinchonidium bromide to form isopropyl-2-(2,4-dimethoxyphenyl)-4-methyl-4,5-dihydro-thiazole-4-(S)-carboxylate in enantiomeric excess.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][CH:45]=O)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:45][CH2:44][CH:41]3[CH2:42][CH2:43][N:38]([C:35]4[CH:34]=[CH:33][C:32]([C:31]([OH:47])=[O:30])=[CH:37][CH:36]=4)[CH2:39][CH2:40]3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCC(CC=O)CC2)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(N2CCC(CCNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-[4-(2-oxo-ethyl)-piperidin-1-yl]-benzoic acid methyl ester. MS (ESI) m/z 610.
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][CH2:16]2)(=O)=O)=CC=1>CS(C)=O>[C:1]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][CH2:16]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCC1COc2ccccc2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
12.53 g (192.5 mmol) of potassium cyanide are added at room temperature to a solution of 55.72 g (175 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman (for manufacture see Example 1) in 300 ml of dimethyl sulphoxide and the whole is heated to 60° while stirring. After 3 hours, ice-water is added to the reaction mixture, the whole is extracted with diethyl ether and washed thoroughly with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 26.75 g (88.3%) of 3-cyanomethylchroman are obtained in the form of a pale yellow oil which crystallises from diethyl ether/pentane. The crystals melt at 63°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[CH:16]=[C:11]3[C:10]([C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:9]2)[CH:5]=[C:4]([CH2:32][CH3:33])[N:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[CH:16]=[C:11]3[C:10]([CH:25]([OH:31])[CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:9]2)[CH:5]=[C:4]([CH2:32][CH3:33])[N:3]=1
Reactant: CCc1cc(-n2cc(C(=O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (150 mg, 0.32 mmol) in a (4:1) mixture EtOH—H2O (4 mL) at −30° C., NaBH4 (70 mg, 1.8 mmol) is added, and the mixture is allowed gradually warm up to room temperature at which the reaction is maintained for 2 h. The mixture is concentrated under reduced pressure, and an aqueous saturated Rochelle's salt solution (10 mL) is added. The resulting suspension is stirred at room temperature for 1 h, and the product is extracted with DCM. The obtained solution is washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[N:3][CH:4]=1
Reactant: Oc1cncnc1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Brc1ccc(Oc2cncnc2)nc1

Procedure:
Educts: 2,5-dibromo-pyridine/5-hydroxypyrimidine using cesium carbonate as base and DMA as solvent
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=1)=O.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])(=[O:25])[CH3:24]>CN1C(=O)CCC1>[C:23]([NH:26][C:27]1[CH:28]=[C:29]([NH:30][C:4]2[N:9]=[C:8]([NH:10][C:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:25])[CH3:24]
Reactant: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NC3(c4ccccc4)CC3)n2)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To a solution of 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in NMP (1 mL) was added 3-acetamidoaniline (27 mg, 0.18 mmol) and pTsO.RH2O (30 mg, 0.16 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (38 mg). MS found for C22H22N6O2 as (M+H)| 403.5. λ=251.1.
Reaction SMILES: [O:1]=[C:2]1[NH:18][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([O:15]CC)=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1>O>[O:1]=[C:2]1[NH:18][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1
Reactant: CCOC(=O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1
Solvent: O
Product: O=C(O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1

Procedure:
The title compound is prepared from ethyl 2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6-carboxylate according to the method described in Example 1/b. Mp.: >270° C. (water).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:13][CH2:12][CH2:11][NH2:14])[CH:7]=1
Reactant: NCCN
Reactant: COc1cc(C)nc(Br)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C)nc(NCCN)c1
Temperature: 120 °C
Yield: 24 %

Procedure:
2-Bromo-6-methyl-4-methoxy-pyridine (202 mg, 1 mmol) was combined with 1,2-ethylenediamine (3 ml) and triethylamin (280 μl, 2 mmol) and heated in a sealed tube at 120° C. for three hours under microwave heating. The mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 2% to 100% acetonitrile) to yield 44 mg of a solid (0.24 mmol, 24%) MS(ESI) m/z=182.1 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:5]2[C@@H:4]2[CH2:23][CH2:24][N:3]12>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=[O:17])=[C:5]2[C@@H:4]2[CH2:23][CH2:24][N:3]12
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
1.77 g (5.4 mmol) of t-butyl (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo [1,5-a][1,4]benzodiazepine-1-carboxylate are stirred in 14 ml of trifluoroacetic acid at 50° for 3 hours and at 65° for 3.5 hours. Subsequently, the mixture is evaporated to dryness and the residue is heated on a steam-bath for 2.5 hours in a high vacuum. The material is treated with ether, stirred for 1 hour while cooling with ice, the solid material is filtered off under suction while back-washing with ether and then dried. There is obtained (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of melting point 232°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[N:31](C4CCCCO4)[N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[CH:28]=[CH:29][NH:30][N:31]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Alternatively, Example 2 was prepared by treating a suspension of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.1, 68.3 g, 132 mmol) in DCM (1 L) with TFA (305 mL, 3959 mmol) at RT for 5.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (2 L), washed with a sat. solution of NaHCO3 (3×500 mL) and brine (2×500 mL), and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the residue was suspended in DCM (300 mL) and stirred at RT for 15 min. The crystalline material was filtered, washed with DCM (200 mL), dried under reduced pressure, dissolved in MeOH (500 mL) and treated with Si-Thiol (Biotage, 10.0 g, 13 mmol) for 15 h at 30° C. The mixture was filtered and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5) and crystallized from MeCN to afford the title compound as a white crystalline solid.