Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH2:28])[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH:28][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 3,5-di-fluoro-phenyl acetic acid (51.6 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.315 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a white solid (56 mg), LC-MS M+1=411.2, 1H NMR(CDCL3) 8.7 (d, 1H,NH), 6.73(m,2H), 6.6(m, 1H), 4.7(m, 1H), 3.5(Abq, 2H), 1.6-1.9(m,2H), 1.3-1.6(m,2H), 1.5(s,9H), 0.92(t,3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=1)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=[C:7]2[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ncc2[nH]1

Procedure:
Route A: To a solution of 3-(2-bromo-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 25, 3.38 g, 10.7 mmol) in THF (50 mL) and ethanol (100 mL) was added saturated ammonium chloride solution (50 mL) and iron powder (3.57 g, 64.0 mmol) and the reaction heated under reflux for 2 h. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The solvent was removed in vacuo and the remainder partitioned between saturated sodium hydrogen carbonate solution (100 mL) and ethyl acetate (3×150 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.42 (3H, t), 4.43 (2H, q), 7.14 (1H, s), 7.85 (1H, s), 8.58 (1H, s); m/z (ES+)=269 [M+H]+. Route B: To a solution of 2-bromo-4-methyl-5-nitropyridine (Preparation 24, 5.7 g, 26.3 mmol) in diethyl oxalate (17.9 mL) under argon was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4.5 mL, 30.2 mmol) to give a dark red precipitate. Reaction mixture was stirred at rt for 4.5 h and concentrated in vacuo. Acetic acid (140 mL) was added to the residue under argon and heated to 60° C. Iron (2.94 g, 52.6 mmol) was added in small portions over a period of 1 h. The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to rt and poured into water (300 mL) which gave a beige precipitate. The precipitate was isolated and washed with water. The solid obtained was dissolved in ethyl acetate (700 ml) and filtered. The filtrate was concentrated in vacuo to give the title compound. m/z (ES+)=269 [M+H]+; RT=3.39 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8]Br.[C-:12]#[N:13].[Na+].[Br-]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH2:8][C:12]#[N:13])[CH:10]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: [C-]#N
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)c(CC#N)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
5-Methoxy-2-bromobenzyl bromide (72.8 g, 0.26 mol) is dissolved in EtOH (280 mL) and stirred at room temperature. Sodium cyanide (38.2 g, 0.78 mol) is dissolved in water and added to the solution of the bromide. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator. A solid forms which is isolated by filtration and washed with water (500 mL). The crude material is purified using flash chromatography (CH2Cl2/hexanes, 1:1) to give 5-methoxy-2-bromophenylacetonitrile (53 g).
Reaction SMILES: Cl.[N:2]1([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[N:36]([C:45](Cl)=[O:46])[C:35]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][C:49]=3[O:58][CH2:59][CH3:60])=[N:34]2)=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH:37]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[N:36]([C:45]([N:5]3[CH2:4][CH2:3][N:2]([S:8]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)(=[O:10])=[O:9])[CH2:7][CH2:6]3)=[O:46])[C:35]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:55])([F:56])[F:57])=[CH:50][C:49]=3[O:58][CH2:59][CH3:60])=[N:34]2)=[CH:29][CH:28]=1
Reactant: O=S(=O)(N1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
4-(Piperazine-1-sulfonyl)-morpholine hydrochloride (0.042 mmol) was suspended in methylene chloride, and 400 uL of diisopropylethylamine was added. The mixture was added to 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (10 mg, 0.019 mmol, example 3), and the reaction mixture was allowed to stand overnight. It was diluted with methylene chloride and washed with water. The organic layer was evaporated, and the residue purified by flash chromatography using ethyl acetate and hexanes to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(morpholine-4-sulfonyl)-piperazin-1-yl]-methanone (9.0 mg). LR-MS: 740.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[N:28]=1.N1CCCCC1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([C:38]2[CH:39]=[CH:40][C:41]([CH:42]=[CH:1][C:2]3[O:3][C:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=3)=[CH:44][CH:45]=2)[N:28]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: COc1ccccc1C1=NN(c2ccc(C=O)cc2)C(c2ccccc2)C1
Solvent: C1CCNCC1
Product: COc1ccccc1C1=NN(c2ccc(C=CC3=CC(=C(C#N)C#N)C=C(c4ccccc4)O3)cc2)C(c2ccccc2)C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 5, 0.197 g (0.84 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.30 g (0.84 mmol) of 4-[3-(2-methoxy-phenyl)-5-phenyl-4,5-dihydro-pyrazol-1-yl]-benzaldehyde were added into 20 ml of alcohol (ethanol), and 0.10 g (1.2 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(=O)N2
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(N1CCN(C)CC1)=N2

Procedure:
In the same manner as in Example 80 and using 8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylanilne, 1-methylpiperazine, 8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:8][N:9]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Cc1ccc2c(O)noc2n1
Product: Cc1ccc2c(OC(=O)N3CCC(C)CC3)noc2n1

Procedure:
In analogy to example 1, 140 mg (0.93 mmol) of 6-methylisoxazolo[5,4-b]pyridin-3-ol were reacted with 181 mg (1.12 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 135 mg (53%), M+H+: 276.10.
Reaction SMILES: CC[O-].[Na+].Cl.[CH3:6][O:7][CH2:8][C:9]([NH2:11])=[NH:10].[C:12]([CH:15]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](OCC)=[O:17])(=O)[CH3:13]>CCO>[CH3:13][C:12]1[N:11]=[C:9]([CH2:8][O:7][CH3:6])[NH:10][C:16](=[O:17])[C:15]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: COCC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)nc(COC)[nH]c1=O
Yield: 41.1 %

Procedure:
A mixture of NaOEt (0.088 mol) in EtOH (prepared from 2.0 g of Na and 70 mL of EtOH), methoxyacetamidine hydrochloride (5.4 g, 0.044 mol), and diethyl acetylglutarate (10.0 g, 0.044 mol) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with ether gave 4.6 g (42%) of product as an off-white solid, mp 87°-90° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH4+:13].[OH-]>O>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: [NH4+]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
4-Fluoro-3-nitrobenzaldehyde (3 g) was slowly added to 50 ml of conc. aq. NH4OH. After stirring for 3 h, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:11][C:5]=2[CH:4]2[O:21][CH:3]12.[H-].[Na+].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>CS(C)=O>[CH3:22][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:13])=[O:14])=[CH:11][C:5]=2[C@@H:4]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[C@@H:3]1[OH:21]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C2OC21
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6.3 g (0.02 mole) of 3,4-dihydro-2,2-di-methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzo[b]pyran in 20 ml of DMSO is added dropwise, at 20°, to a suspension of 0.6 g (0.02 mole) of 80% NaH in 10 ml of DMSO. Then 2.3 ml (0.03 mole) of 2-pyrrolidinone are added, and the mixture is stirred at 45° for one hour. After it has stood at 20° overnight it is introduced into ice-water. The precipitate is filtered off with suction, washed to neutrality, dried and chromatographed on silica gel with methylene chloride/methanol 19:1. 30 ml fractions are collected. Fractions 12-22 are concentrated, and the residue is recrystallized from acetonitrile.
Reaction SMILES: NC1CC[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CC1.C(N(CC)CC)C.ClC(OC[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1)=O>O1CCCC1>[CH3:29][CH2:28][CH2:27][CH2:32][CH2:31][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:9][CH2:8][NH2:5]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a 0° C. solution of 4-amino-1-benzylpiperidine 11 (41.2 g, 216.5 mmol) and triethylamine (51.3 mL, 369 mmol) in 600 mL of tetrahydrofuran was added benzyl chloroformate (31 mL, 217 mmol) dropwise over a period of 30 to 45 min. at such a rate that the reaction temperature was kept between 5° C. and 10° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stir for 12 hours. The solvent and volatiles were removed under reduced pressure. Water (500 mL) and ethyl acetate (1.2 L) were then added and the reaction was partitioned between the two phases. The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×, 150 mL) and then dried (brine, MgSO4). Evaporation of the solvent yielded a tan liquid which was purified via column chromatography (SiO2, EtOAc/Hexane-30/70 to EtOAc-100) to provide 27.8 g of the amine 12 as a white solid (mass spec. M+=324, MP=79.1-79.6° C.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:7])C.O1CCCC1>CO>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:6]([OH:7])=[O:5])=[C:16]2[CH3:17]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2N NaOH (20 mL) was added to a suspension of 5-chloro-3-methyl-1H-indole-2-carboxylic acid ethyl ester (7.0 g, 29.4 mmol) in methanol (50 mL) and the resulting mixture stirred at 25° C. for 18 hours. Tetrahydrofuran (100 mL) was added and the resulting solution heated at reflux for 30 minutes and concentrated. The residue was dissolved in water and the resulting solution extracted twice with ethyl acetate. The aqueous layer was acidified and the precipitate collected by filtration and washed with water (5.24 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:3]=2)[CH:19]=[N:18]1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
A mixture of 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (0.50 g, 2.25 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.25 mmol), and Cs2CO3 (1.46 g, 4.49 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.26 g, 0.23 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration, washed with dioxane and the filtrate concentrated to dryness. The residue was treated with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to dryness. The material was treated with EtOAc and the resulting solid collected via filtration to afford 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.41 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, 1 H), 8.44 (s, 1 H), 8.12 (s, 1 H), 7.78 (d, 1 H), 7.28 (m, 2 H), 6.48 (d, 1 H), 5.94 (s, 2 H), 3.88 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A mixture of 2-bromopyridine (6.37 g, 35 mmol), 2-fluorobenzeneboronic acid (6.86 g, 49 mmol) and 2 M sodium carbonate solution (35 mL, 70 mmol) in THF (70 mL) was degassed with nitrogen for 20 min. Tetrakis(triphenyl-phosphine)palladium(0) (1.21 g, 1.1 mmol) was added, and the mixture was stirred at reflux under nitrogen for 36 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate and sodium carbonate. The organic phase was washed with water and then with saturated sodium hydrogencarbonate solution, was dried over magnesium sulfate and then was absorbed on to silica gel. Purification by flash chromatography on silica gel, eluting with isohexane (+0.5% triethylamine and 0.5% MeOH) on a gradient of diethyl ether (5% to 20%) afforded 2-(2-fluorophenyl)pyridine as a yellow oil which crystallised upon standing (5.5 g, 91%). δH (400 MHz, CDCl3) 7.13-7.19 (1H, m), 7.24-7.28 (2H, m), 7.35-7.41 (1H, m), 7.73-7.81 (2H, m), 7.97 (1H, ddd, J 8, 8 and 2), 8.72-8.74 (1H, m); m/z (ES+) 174 (M++H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[N:15][NH2:16])[CH3:6]
Reactant: NN
Reactant: CON=C(C(C)=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: CON=C(C(C)=NN)c1ccccc1
Yield: 56 %

Procedure:
2.5 g (0.014 mol) of 1-phenylpropane-1,2-dione 1-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 1.45 g (0.029 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with diethyl ether and the crystals are filtered off. 1.5 g (55.6% of theory) of 2-hydrazono-1-phenylpropan-1-one O-methyl oxime of melting point 132° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH:43]([Cl:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH:43]([Cl:47])[C:44]([NH:20][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(N)C(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)C(Cl)Cl)C(C)(C)C)CC1
Yield: 59.6 %

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate, example 915, (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2,2-dimethylpropyl}acetamide (0.036 g, 60%) as an oil. ES-LCMS m/z 670 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.[CH3:29][N:30]([CH2:32]N(C)C)[CH3:31].C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:29][N:30]([CH3:32])[CH3:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:6]=2[CH:28]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cc3ccccc3)n1-2
Reactant: CN(C)CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)CC(c1ccccc1)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C

Procedure:
A stirred solution of 8-chloro-1-benzyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.85 g., 0.01 mole) in dry dimethylformamide (50 ml.) was cooled, under nitrogen, in an ice bath and treated with N,N,N',N',-tetramethyldiaminomethane (1.229 g., 0.012 mole) and then dropwise with acetyl chloride (0.923 ml., 0.013 mole). The mixture was kept in the ice bath for 2 hours, poured into a mixture of ice and saturated aqueous sodium bicarbonate solution and extracted several times with chloroform. The extracts were washed with a dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove dimethylformamide. The residue was chromatographed on silica gel (200 g.) with methanol. The product thus obtained was crystallized from diethylether to give 8-chloro-1-[2-(dimethylamino)-1-phenylethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in six crops; 0.483 g. of melting point 168.5°-170° C; 1.436 g. of melting point 169°-170.5° C. and 0.471 g. of melting point 169°-170.5° C., 0.530 g. of melting point 168.5°-170° C.; 0.231 g. of melting point 169°-170° C. and 0.269 g. of melting point 169°-170.5° C. The analytical sample was crystallized from ethyl acetate-Skellysolve B hexanes and had a melting point of 169.5°-171.5° C.