Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1.[N:34]([C@@H:37]([C@H:41]([C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=1)[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[C:38](O)=[O:39])=[N+:35]=[N-:36].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:34]([C@@H:37]([C@@H:41]([C:42]1[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=1)[C:49]1[CH:50]=[C:51]([F:56])[CH:52]=[C:53]([F:55])[CH:54]=1)[C:38]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:11]1)=[O:39])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,5R)-2-(2-(3-amino-5-fluoropyridin-4-yl)ethyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-4-carboxylate (Example 89, step 4) (64 mg, 0.13 mmol) and (2S,3S)-2-azido-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoic acid (43 mg, 0.13 mmol) in pyridine (0.5 mL) was cooled to −10° C. in an ice-acetone bath. To the stirred solution was added POCl3 (0.014 mL, 0.15 mmol) and the mixture was stirred for 30 min. The reaction was quenched by the addition of aqueous NaHCO3 solution and the resulting mixture was extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-80% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.48 min, M+H=784 (2 min gradient)
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:19][CH2:18][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: COc1ncnc2c1CNCC2
Yield: 96.9 %

Procedure:
250 mL flask was charged with 6-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (4.08 g, 16.0 mmol), 10% palladium on charcoal (400 mg) and methanol (100 mL). The reaction was evacuated and purged with hydrogen three times, and hydrogenated (1 atm) overnight. The mixture was filtered through a “Dry disk” membrane filter, and concentrated in vacuo to yield an orange oil (2.56 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued. The precipitated morpholine hydrochloride was filtered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[N:24]=[C:25]([C:32]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH2:44][CH2:45][CH3:46])[C:39](=[O:47])[N:38]([CH2:48][CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[C:37]3=[O:58])=[O:33])[N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12>O.CN1C(=O)CCC1.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>[F:57][C:54]1[CH:53]=[CH:52][C:51]([O:50][CH2:49][CH2:48][N:38]2[C:37](=[O:58])[C:36]3[C:41](=[CH:42][CH:43]=[C:34]([C:32]([C:25]4[N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]5=[C:23]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:3]([O:2][CH3:1])=[O:4])[N:24]=4)=[O:33])[CH:35]=3)[N:40]([CH2:44][CH2:45][CH3:46])[C:39]2=[O:47])=[CH:56][CH:55]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)OC)c4)c4ccccn34)ccc21
Temperature: 120 °C
Yield: 69.1 %

Procedure:
2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g (20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and 582.4 g (0.504 mmol) of tetrakis(triphenylphosphine)palladium are added to 5.7 g (10.08 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione in 180 ml of NMP. The reaction medium is microwave-heated for 15 minutes at 120° C. and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (100/1) mixture. 4.32 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: Nc1ccccc1
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 76.9 %

Procedure:
In a similar manner as described in step 1 of Example 8, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.50 g, 4.71 mmol), prepared in step 3 of Example 1, and aniline (3.07 g, 33.0 mmol). Purification on silica gel (500 g, 200–300 mesh) using 0% to 50% methylene chloride in hexane as the eluent gave 2-(6-methoxy-2-naphthyl)-1,5-diphenyl-1H-pyrrole as an off-white solid (1.36 g, 77%), mp 199–200° C. Elemental Analysis for C27H21NO.0.11 CH2Cl2 Calc'd: C, 84.62; H, 5.56; N, 3.64. Found: C, 84.55; H, 5.67; N, 3.61.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[CH:28]=[CH:27][S:26][CH:25]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3cc(F)ccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.1 g (0.34 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.77 mL (0.45 mmol) of a freshly prepared 0.58 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.13 g (100% of yield) 4-(6-fluoro-1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=O)[CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: O=CNCc1cc(Br)ccn1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccn2cncc2c1
Temperature: 25 °C

Procedure:
A solution of 10.75 g of N-(4-bromopyridin-2-ylmethyl)formamide in 100 ml of benzene is admixed with 8.43 g of phosphorus oxychloride. The reaction mixture is heated to reflux over 4 hours. The reaction mixture is subsequently cooled to room temperature and concentrated by evaporation, and the residue is admixed with 200 ml of water. The aqueous solution is basified with 1M NaOH and extracted with dichloromethane (3×300 ml). The combined organic phases are washed with 300 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].N1C=CC=CC=1.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>CN(C)C1C=CN=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CCCCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCCCl
Yield: 73 %

Procedure:
A mixture comprising 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), tert-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8.2 mmol) was heated at 50° C. under an atmosphere of dry nitrogen for 12 hours to give a white suspension. The suspension was partitioned between ethyl ether (250 mL) and water and the organic layer was separated and washed repeatedly with water then 0.1M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a colorless oil. The oil was distilled at 0.5 mmHg (51° C.) to provide tert-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1H NMR (300 MHz, CDCl3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH2:17]O)[CH:10]=[N:9]1)([CH3:7])[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:11]1[CH:10]=[N:9][N:8]([CH:5]([CH3:7])[CH3:6])[C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)n1ncc(CO)c1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1ncc(CCl)c1C(F)(F)F
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Thionyl chloride (5.26 mL, 72 mmol) was added to [1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanol (Preparation 105, 7.5 g, 36 mmol) in DCM (75 mL) at 0° C. and the mixture was stirred for 2 hours. The mixture was diluted with DCM (30 mL) and the organic phase was washed with water (75 mL), brine (75 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford 4-(chloromethyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole (86%, 7 g).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][C:35]=1[Cl:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[Cl:36])[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dichlorophenol (8.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.20 mg, 39.7% yield) as a thick oil: 1H NMR (CDCl3) δ 7.70-7.63 (m, 2H), 7.55 (m, 1H), 7.47-7.43 (m, 3H), 7.40-7.19 (m, 3H), 7.00-6.50 (m, 2H), 6.69 (dd, 1H, J=2.2, 8.8 Hz), 5.25 (m, 1H), 3.20 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.40-2.20 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: C(OC[N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[N:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH:38]5[CH2:40][CH2:39]5)=[CH:33][N:32]=4)[CH2:27][CH2:26]3)=[O:24])=[C:19]([F:41])[CH:18]=2)[C:11]1=[O:42])C1C=CC=CC=1.C(O)=O>CO.[C].[Pd]>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:12]5[CH:13]([CH3:16])[C:14](=[O:15])[NH:10][C:11]5=[O:42])=[CH:18][C:19]=4[F:41])=[O:24])[CH2:26][CH2:27]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)cc2F)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)NC(=O)C3C)cc2F)CC1
Yield: 18.8 %

Procedure:
3-Benzyloxymethyl-1-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methylimidazolidine-2,4-dione (270 mg) described in Example 536 was dissolved in methanol (20 mL), formic acid (0.36 ml) and 10% palladium carbon catalyst (108 mg) were added, and the mixture was stirred with heating under reflux for 16 hr. The reaction mixture was cooled, the catalyst was removed by celite filtration, and the solvent was evaporated. To the residue were added methanol and 0.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature. The reaction solution was neutralized with acetic acid, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][NH:15]1.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:18]=1[CH2:17][CH2:16][NH:15][C:14]2=[O:13]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 5-methoxy-1,3-dihydro-indol-2-one (32.6 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([N:21]1[CH2:22][CH2:23][N:24]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][C:5]=3[F:16])[NH:9][CH:8]=2)=[O:15])[C@H:19]([CH3:18])[CH2:20]1)=[O:32]
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)ncc(F)c12
Reactant: C[C@@H]1CN(C(=O)c2ccccn2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)ncc(F)c12

Procedure:
Precursor 5o, (R)-1-picolinoyl-3-methyl-4-[(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-4-fluoro-6-azaindol-3-yl)oxoacetate, Precursor 4h, and (R)-3-methyl-1-picolinoyl-piperazine. 1H NMR (500 MHz, CD3OD) δ8.68-7.52 (m, 6H), 4.94-2.69 (m, 7H), 1.48-1.24 (m, 3H). MS m/z: (M+H)+ Calc'd for C20H18BrFN5O3: 474.06; Found 474.23. HPLC retention time: 1.20 minutes (column A).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O>C1COCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Saturated aqueous potassium carbonate (190 mL) and 4-methoxybenzoyl chloride (60.8 g, 358 mmol) were added to a solution of glycine methyl ester (30.0 g, 239 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and then poured into water (100 mL). The resulting mixture was extracted with EtOAc (200 ml×2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to afford methyl 2-(4-methoxybenzamido)acetate (46.2 g, 86% yield) as a colorless solid, which was used directly without further purification.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccnc1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with pyridine-3-yl-boronic acid to give the title compound as light yellow amorphous solid. MS: 484.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)#[N:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:31]5[CH:30]=[C:29]([C:27]#[N:28])[CH:34]=[CH:33][C:32]=5[F:38])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(C#N)ccc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-cyano-2-fluoro-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.84 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[O:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C([O-])(=[O:24])C.[Na+].O>C(O)(=O)C>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:24])[NH:7][N:6]=3)[CH:21]=[CH:20][C:11]=2[N:12]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc(-c2ccc3nc(-c4cccs4)oc3c2)nn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc3nc(-c4cccs4)oc3c2)n[nH]1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
550 mg (1.75 mmol) 6-(6-chloro-pyridazin-3-yl)-2-thiophen-2-yl-benzoxazole in 15 mL glacial acetic acid are placed under protective gas in a pressurised vessel, 173 mg (2.11 mmol) sodium acetate are added and the mixture is stirred for 4 days at 120° C. The reaction mixture is combined with H2O and extracted with DCM. The solv. of the org. phase is eliminated i.V. The residue is suspended in ACN and a solid is suction filtered. The solid is suspended in DCM, stirred for 2 h at RT and suction filtered again.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1>[Ni].CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A suspension of 1-(4-methoxy-benzyl)-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step 111.2) (0.635 g, 1.85 mmol) and Raney Nickel (0.150 g) in MeOH/THF (1:1, v/v; 50 mL) was stirred for 24 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1) to afford 439 mg of the title compound as a white solid. Title compound: ESI-MS: 313.3 [M+H]+; tR=1.40 min (System 1); TLC: Rf=0.18 (DCM/MeOH, 9:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:42])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:41]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:18]=[CH:17][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:42])=[CH:21][CH:20]=4)=[N:41][C:27]2=3)[CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3)ncc21
Reaction time: 1 h
Yield: 760.5 %

Procedure:
A mixture of 0.075 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.048 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-benzamide (I-14).