Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[S:11][C:12]([CH3:17])=[CH:13][C:14]=2[C:15]#[N:16])=[C:4]([N+:18]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:24].Cl>C(O)C>[ClH:24].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:18]=[C:15]([NH2:16])[C:14]3[CH:13]=[C:12]([CH3:17])[S:11][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: Cc1cc(C#N)c(Nc2cc(F)c(F)cc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Temperature: 86.5 °C
Yield: 99.7 %

Procedure:
Add 2-(4,5-difluoro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (94.0 g, 318 mmol) and tin (II) chloride dihydrate (225 g, 997 mmol) to ethanol (1400 mL) and aqueous 6N HCl (1400 mL) with stirring under nitrogen. Heat at gentle reflux (86-87° C.) for 0.3 hours, and then allow cooling to ambient temperature. Filter, rinse with water (3×250 mL) and dry at 50-60° C. to give 95.7 g (100%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (bs, 1H), 9.84 (bs, 1H), 9.33 (bs, 1H), 8.93 (bs, 1H), 7.00 (m, 2H), 6.85 (s, 1H), 2.28 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9F2N3S (freebase) 266.0563; found 266.0555.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Cl[C:27]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:29]([C:28]1[CH:27]=[CH:34][C:33]([OH:35])=[CH:32][C:31]=1[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])[N:15]=[CH:16]2)=[CH:11][CH:10]=1)#[N:30]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)C4CC4)ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 120 °C
Yield: 91.1 %

Procedure:
A mixture of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (48 mg, 0.1 mmol), 2-chloro-4-hydroxybenzonitrile (45 mg, 0.3 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mg, 0.015 mmol), and saturated aqueous sodium carbonate (0.1 mL) in acetonitrile (1 mL) was heated under microwave irradiation (Biotage, 200 watts) at 120° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (30 mg, 60%). 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 10.95-10.68 (brs, 1H), 9.23 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 6.97 (dd, J=8.5, 2.2 Hz, 1H), 2.14-2.03 (m, 1H), 0.94-0.77 (m, 4H). LCMS (Method E): RT=4.137 min, M+H+=330.1.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) in 1,2-dichloroethane (5 mL) was added acetic acid (0.2 mmol), formaldehyde (37% water solution, 0.037 mL), and NaBH(OAc)3 (0.2 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded 0.015 g of the title compound. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.27 (s, 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[S:16]1[CH2:18][CH2:17]1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17][SH:16])[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CS1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CN(C)C=O
Product: SCCN1CCN(c2cccc3[nH]ccc23)CC1
Yield: 43.4 %

Procedure:
1-(1H-Indol-4-yl)piperazine (3.9 g) and thiirane (1.75 g) was dissolved in DMF (200 mL) and refluxed for 1 h. The mixture was evaporated and re-dissolved in TBF, dried with MgSO4, filtered and evaporated to give the an oil which was subjected to purification by column chromatography (silica gel; ethyl acetate and heptane) giving the title compound as an oil (2,2 g). MS m/z (%): 261 (MH+, 100%), 202 (100%), 159 (23%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>ClCCl.CN(C=O)C.O1CCOCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([NH2:24])=[O:17])[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 500 mg, 2.17 mmol) in dichloromethane (15 mL) was added dropwise oxalylchloride (950 μL, 10.9 mmol) and one drop DMF. After stirring at rt for 1 h, all volatiles were removed in vacuo. The crude acid chloride thus obtained was re-dissolved in dioxane (10 mL) and added dropwise to aqueous ammonia (33%, 6.4 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at rt for 30 minutes. A white precipitate formed which was collected by filtration and washed with water. The title compound was obtained after drying in vacuo (436 mg, 89%): 1H NMR (400 MHz, DMSO-d6) δ 7.37 (broad s, 1H), 7.14 (d, 2H, and broad s, 1H), 7.02 (d, 2H), 6.43 (s, 1H), 5.28 (s, 2H), 2.27 (s, 3H), 2.19 (s, 3H); ES-MS m/z 230 (MH)+; HPLC RT (Method E) 1.39 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[CH2:26][CH2:27][O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:26][CH2:27][O:28][CH3:29])[N:15]=[CH:16][N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3O)ncn2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccccc1-c1cc(Nc2cccc(S(C)(=O)=O)c2)ncn1

Procedure:
A mixture of 2-[6-(3-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-phenol (reference example 49) (0.31 g, 0.94 mmol), 1-bromo-2-methoxy-ethane (0.516 g, 3.75 mmol), potassium carbonate (1.03 g, 7.5 mmol) and acetonitrile (15 mL) was refluxed for 8 h. Then the reaction mixture was evaporated, the residue was washed with water and purified by column chromatography on silica (eluent chloroform-ethanol 20:1) to give (3-methanesulfonyl-phenyl)-{6-[2-(2-methoxy-ethoxy)-phenyl}-pyrimidin-4-yl]-amine as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1)=[O:4].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[CH3:20]
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
tert-Butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V, (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl) propan-1-one (0.34 g, 0.85 mmol), Boc-L-Tic-OH (Peptech Corp.) (0.26 g, 0.93 mmol), EDC (0.2 g, 1.0 mmol), HOBT (used in place of HOAT) (Bachem) (0.14 g, 0.93 mmol) and CH2Cl2 (4 mL). The crude compound was purified on a Biotage 40S column (CH2Cl2/MeOH 95:5) to give tert-butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate as a white foam (0.32 g). MS m/z: 660 (M+H). Calc'd for C37H46ClN5O4: 660.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH:7]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH:7]([N:20]1[CH2:25][CH2:24][N:23]([CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
Methylbromoacetate (2,75 g, 18 mmol) was added dropwise to a solution of benzhydrylpiperazin (4.5 g, 18 mmol) in THF (150 ml). The reaction was stirred for 30 minutes at room temperature and a white precipitate formed. THF was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution and water before drying over magnesium sulphate, filtration and removal of solvent to leave (4-benzhydrylpiperazin-1-yl)-acetic acid, methyl ester as a pale brown oil (2.80 g, 48%).
Reaction SMILES: CNC.[CH3:4][N:5]([CH:7]=[O:8])[CH3:6].[F:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC2C=CC=CC=2)=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1>O>[F:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:7](=[O:8])[N:5]([CH3:6])[CH3:4])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1
Reactant: CN(C)C=O
Reactant: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Agent: CNC
Solvent: O
Product: CN(C)C(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A 50% dimethylamine aqueous solution (2.5 ml) was added to a DMF solution (25 ml) of phenyl [3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (5.89 g, 17.6 mmol), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution twice, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=19:1→4:1→2:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 4.10 g of oily pale yellow 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (yield: 82%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:17]([CH3:16])[C:18]#[CH:19])[N:3]=[CH:4][N:5]=1
Reactant: C#CC(C)O
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 150 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 56 mg of 3-butyn-2-ol, to which 32 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 120 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (134)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:36][CH2:37][N:38]([CH2:14][CH2:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:39][CH2:40]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2cc(C(=O)CC3CCNCC3)c3ccccc3n2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)CC3CCN(CCc4ccccc4)CC3)c3ccccc3n2)cc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
3.45 g of potassium carbonate and 1.39 g of 2-phenylethyl bromide are added to a solution of 1.72 g of 1-[2-(4-methyl-phenyl)-4-quinolyl]-2-(4-piperidyl)-ethanone, prepared as indicated in Example 8, in 25 ml of dimethylformamide. The suspension, well stirred, is heated for 5 hours at 60° C., then poured into 1 liter of ice-water. The oil which separates is decanted, washed with water, then 100 ml of ether and 100 ml of a 1 N aqueous solution of hydrochloric acid are added. The precipitate formed is filtered, washed with water and then with acetone. 2 g of 1[2-(4-methyl-phenyl)-4-quinolyl]-2-[1-(2-phenyl-ethyl)-4-piperidyl]-ethanone are obtained in the form of dihydrochloride melting at 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1>>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:15]2[C:16](=[O:19])[CH2:17][CH2:18][N:12]([C:10](=[O:11])/[CH:9]=[CH:8]/[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:14]2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(CCCl)CC1
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Product: CC(=O)N1CCN(CCN2CCN(C(=O)/C=C/c3cccc(Cl)c3)CCC2=O)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-[4-(2-chloro-ethyl)-piperazin-1-yl]-ethanone gave the title compound as off-white foam. MS: 433.2 (MH+, Cl).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:11](=[O:15])[CH2:12][CH2:13]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)CCCl)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1ccc2c(c1)CCC2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 18.7 %

Procedure:
1-(4-tert-Butyl-phenyl)-3-chloro-propan-1-one (45.6 g, 447 mmol) was taken up in concentrated sulfuric acid (200 mL) and the resulting mixture was heated to 100° C. with stirring for 2.5 hours. TLC indicated that all of the starting material had been consumed. After cooling to room temperature, the reaction mixture was very carefully poured onto about 1 Kg of crushed ice. Then some diethyl ether was added and the mixture was stirred carefully until it had cooled to about room temperature. Ethyl acetate (1200 mL) was added and after partitioning, the layers were separated. The acidic layer was then further extracted with ethyl acetate (2×200 mL). The combined ethyl acetate layers were washed with saturated sodium bicarbonate (5×300 mL). Finally the ethyl acetate layer was dried over magnesium sulfate, filtered, concentrated and pumped to dryness to afford the title compound as a colorless oil (15.764 g).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][OH:31])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>[Pd].C(O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][OH:31])=[O:24])[NH2:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
30 mg of palladium on activated carbon (10%) are added to a mixture of 0.164 g (0.29 mmol) of the compound from Example 248A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[N:34]([CH3:35])[C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[N:34]([CH3:35])[C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cn1c(C#N)ccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 32.1 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid to afford an off-white powder. HPLC (Condition 4) tR=5.96 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=486 [M−H]−.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].[C:16]12([CH3:26])[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][C:17]2=O.[OH-].[K+].Cl>CO>[CH3:26][C:16]12[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:17]2[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:3]1[C:4]([CH3:9])([CH3:10])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CC(=O)C=CC1C2(C)CCC(C2)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC12CCC(C1)C(C)(C)C2CCC(=O)CC1CC2CCC1(C)C2(C)C
Temperature: 20 °C

Procedure:
20.6 gm. (0.1 mole) of 1-(1,3,3-trimethylbicyclo-[2.2.1]hept-2-yl)-1-buten-3-one and 18.3 gm. (0.12 mole) of camphor is dissolved in 25 ml. methyl alcohol. A solution of 3.4 gm. of potassium hydroxide in 20 ml. of methyl alcohol is then added over a period of 15 minutes using good agitation and external cooling. The reaction mixture is maintained at 40°-45° C. for 6 hours, cooled to 20° C., made slightly acid by the addition of dilute hydrochloric acid and the residue after solvent stripping under reduced pressure extracted with ether. The ether solution is washed two times with one-tenth its volume of cold water, dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure. The residual oil which contained 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)but-3-en-2-one is dissolved in 100 ml. of thiophene-free benzene and shaken under 50 psi hydrogen pressure in the presence of 3 gm. 5% palladium on carbon at 25° C. until slightly more than theoretical hydrogen uptake is observed. The catalyst is removed by filtration and the solvent stripped. The residual oil is purified by fractional distillation under reduced pressure to provide the 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)butan-2-one.
Reaction SMILES: [Li+].[Cl-].[C:3]([N:6]1[CH2:11][CH:10]=[C:9]([Sn](CCCC)(CCCC)CCCC)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]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>[C:3]([N:6]1[CH2:11][CH:10]=[C:9]([C:3]2[C:4]3[CH:30]=[CH:29][O:28][C:27]=3[CH:26]=[CH:7][N:6]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Product: CC(=O)N1CC=C(c2nccc3occc23)CC1
Temperature: 100 °C

Procedure:
7 equivalents of LiCl, and then 0.03 equivalents of Pd(PPh3)4 are added, under a stream of argon, to a solution of 52.3 mmol of the product of Preparation 1 and 1.2 equivalents of the product obtained in Step B in 800 ml of dioxane. The reaction mixture is heated to 100° C. and 0.03 equivalent of Pd(PPh3)4 is added in succession, after reaction for 12 hours, 24 hours and 48 hours, and the reaction mixture is maintained at 100° C. for an additional 24 hours. After cooling, filtration over Celite and concentration under reduced pressure, chromatography of the residue on silica gel (dichloromethane/ethanol: 97/3) enables the expected product to be isolated; the product is then crystallised in pentane.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)n1)N1CCNCC1

Procedure:
Compound 74 was dissolved in DCM (5 mL) and TFA (1.5 mL) and stirred at 20° C. for 2.5 hrs. The reaction was concentrated in vacuum and purified by preparative HPLC eluting with a gradient 10% MeCN/water/0.1% TFA-50% MeCN/water/0.1% TFA to provide compound 71 (23 mg) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 9.63 (1H, s), 9.32 (1H, s), 8.68 (1H, d, J=6.1 Hz), 8.63 (1H, d, J=6.4 Hz), 7.84 (1H, s), 5.56 (1H, p, J=8.1), 4.00-4.29 (4H, br s), 3.39 (4H, t, J=5.3 Hz), 2.63 (2H, m), 2.25 (4H, m), 1.98 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 449.2.