Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].O.Cl>N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(C)=CCc1cc(C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1CC=C(C)C
Reaction time: 48 h
Yield: 51 %

Procedure:
Acetic anhydride (1 mL) was added dropwise to a solution of acid 8 (178 mg, 2.00 mmol) in pyridine (3 mL) at room temperature. After stirring for 48 hours, the mixture was poured into water (6 mL) and acidified to pH=2 by the dropwise addition of 6 M HCl. The suspension was extracted with EtOAc (2×10 mL), and the combined organic fractions were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (5:1, hexanes:EtOAc) to afford acetate 9 (223 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.96 (m, 2H), 7.15 (dd, J=3.5, 8.2 Hz, 1H), 5.24 (tt, J=1.3, 7.2 Hz, 1H), 3.30 (d, J=7.2 Hz, 2H), 2.34 (s, 3H), 1.97 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:5]4[S:1][C:2](=[O:7])[NH:3][C:4]4=[O:6])=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:9][CH2:10]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=C3SC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
In a reaction flask, thiazolidine-2,4-dione (9 mg, 0.08 mmol) and 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (15 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (8 uL, 0.08 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (10 mg, 54% yield). LCMS (M+1=502)
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:26]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[C:10]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.18 (d, J=2.0 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.61 (dd, J=7.8, 2.9 Hz, 3H), 7.48-7.30 (m, 4H), 7.24-7.10 (m, 5H), 6.73-6.68 (m, 2H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.81 (s, 4H), 2.36 (s, 3H), 1.50 (s, 9H), MS (ES) m/e 562 M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:24]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:15][CH2:8][CH2:9][CH3:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 313.8 %

Procedure:
Potassium carbonate (24.8 g, 180 mmol) was added to a solution of 4-hydroxybenzaldehyde (3.66 g, 30 mmol) in DMF (90 mL) at room temperature. After the mixture was stirred at 60° C. for 1 h, 1-bromooctane (8.7 mL, 36 mmol) was added slowly. The reaction mixture was stirred overnight at 80° C. under N2, cooled to room temperature, and poured over 200 mL of icy water. The mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give a yellow oil (13.67 g). 1H NMR (400 MHz, CDCl3, δ): 9.88 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.06 (t, J=6.6 Hz, 2H), 1.83-1.76 (m, 2H), 1.62-1.23 (m, 18H), 0.90 (t, J=8.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].Cl>CCOCC.O.CC(CC)=O>[OH:19][CH2:18][CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(SCCO)cc1

Procedure:
11.2 g (0.05 mol) of 4-chlorobenzophenone, 4.3 g (0.055 mol) of 2-mercaptoethanol, 13.8 g (0.1 mol) of calcined K2CO3 and 15 ml of ethyl methyl ketone are warmed (under reflux) for 16 hours under nitrogen. 50 ml of water are poured over the cooled reaction mixture and the resulting mixture is acidified with HCl. The product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The product, which in this case also is obtained as an oil, crystallises on standing. It is boiled up in hexane as described in (a). Yield: 10.0 g (77%). Melting point 49°-51°.
Reaction SMILES: [F:1][CH2:2][CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:3][CH2:2][F:1])=[CH:42][CH:43]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 54 mg 1-fluoro-2-iodoethane (0.31 mmol) in N,N-dimethylformamide (10 mL) was subsequently added 101 mg potassium carbonate (0.73 mmol), followed by 100 mg di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(4-hydroxybenzyl)-hexanedioate (from example 12d; 0.21 mmol), and the resulting mixture was stirred for 4 h at room temperature. The mixture was then partitioned between water and ethyl acetate, the aqueous layer was than extracted with ethyl acetate again. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC, method A to give 85 mg (62% purity adjusted yield) of the target compound in approx. 80% purity.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]3=[O:32])=[CH:17][C:16]=2[F:33])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:34]([CH2:26][C@@H:24]1[O:23][C:22](=[O:32])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:13]3[CH:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[N:11]=[CH:12]3)=[C:16]([F:33])[CH:17]=2)[CH2:25]1)=[N+:35]=[N-:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
(5R)-3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (13.6 g) was dissolved in dry N,N-dimethylformamide (110 ml). Sodium azide (3.53 g) was added, and the mixture was heated at 80° C. for 3.5 hours. The mixture was cooled, diluted with water (1.1 L) containing sodium bicarbonate (2 g), and extracted with ethyl acetate (2×800 ml). Combined organics were washed with water (2×300 ml), then brine, and dried over magnesium sulfate. The solution was evaporated to a small volume (˜100 ml), and insolubles filtered. The ethyl acetate soluble material was columned on silica (100 g), eluting with ethyl acetate. Product fractions were combined and evaporated to give a gum (10.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.N.CO.O>[Fe].CC(=O)OCC>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c([N+](=O)[O-])cc23)c1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c(N)cc23)c1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
(S)—N-(3-ethynylphenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine (4 g, 0.011 mol) and ammonia hydrochloride (2.4 g, 0.045 mol) was mixed in a solution of 150 mL methanol, 75 mL H2O, 50 ml EA, and then was heated to 70° C. Fe (4.8 g, 0.085 mol) was added and the reaction mixture was heated to reflux for 4 hours. The resulting reaction solution was filtered and concentrated under reduced pressure to remove most of solvent. The residue was diluted in 100 mL H2O, extracted with ethyl acetate (3×100 mL), the organic layers were concentrated to give (S)—N4-(3-ethynylphenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine as grey solid 1.8 g (48.9% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31](=[O:40])[C:32]([CH3:39])=[CH:33][NH:34]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:30]=3[C:31](=[O:40])[C:32]([CH3:39])=[CH:33][NH:34]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Cc1c[nH]c2cccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4[nH]cc(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 5-amino-3-methylquinolin-4(1H)-one (Compound 203A). 1H NMR (DMSO-d6, 400 MHz): δ=1.18 (t, J=7.07 Hz, 6H), 2.00 (s, 3H), 3.15-3.25 (m, 2H), 3.96 (qd, J=7.37, 7.20 Hz, 4H), 7.16 (d, J=7.83 Hz, 1H), 7.24 (dd, J=8.59, 2.27 Hz, 2H), 7.51 (t, J=7.96 Hz, 1H), 7.61 (d, J=6.82 Hz, 2H), 7.97 (d, J=5.81 Hz, 1H), 8.45 (s, 1H), 8.71 (br. s., 1H), 9.84 (s, 1H), 12.01 (d, J=6.06 Hz, 1H), 14.42 (br. s., 1H). MS (ES+): m/z 562.13 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]4)=[O:15])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: CC1(C)COc2cccc(Oc3ccc(N)cn3)c21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (Intermediate 68, 20.16 mg) in dry N,Ndimethylformamide (3 ml), DIPEA (20.44 μl, 0.117 mmol) and then HATU (35.6 mg, 0.094 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinamine Intermediate 59, 20 mg) was added and the reaction mixture was stirred at 60° C. under argon during 12 hours. The reaction mixture was cooled down and a prestirred (15 min) solution of HATU (1 equiv), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (1 equiv) and DIPEA (1 equiv) in 1 mL of dry DMF was added. The reaction mixture was heated under argon an additional 12 hours at 60° C. The reaction mixture was evaporated. The residue obtained was purified on silica gel (Companion instrument) with cyclohexane/ethylacetate as eluents from 100/0 to 70/30. This afforded the title compound (14 mg)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[N:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: CCc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 4.00 g of 1-(4-ethylphenyliminomethyl)-2-nitroiminoimidazolidine, 3.00 g of 2-chloro-5-chloromethylpyridine, 4.20 g of potassium carbonate, and 10 ml of DMSO was agitated at 60° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to give an oily residue, followed by purification with column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to obtain 2.70 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(4-ethylphenyliminomethyl)imidazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16].C=O.[C:43](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:43])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16]
Reactant: CC(=O)O
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCN(C)CC2)c1Cl
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Example 47, 230 mg, 0.40 mmol) in DCM (4 mL) and MeOH (2 mL) was added formaldehyde (0.033 mL, 1.2 mmol) and acetic acid (0.046 mL, 0.80 mmol) followed by sodium triacetoxy borohydride (0.17 g, 0.80 mmol). The solution was stirred for 1 h. The solution was diluted with DCM (20 mL) and washed with sat'd NaHCO3 solution (10 mL). The organic layers were dried (MgSO4), filtered and the solvent removed on a rotovap. The residue was dissolved in DCM and loaded onto a 4 g ISCO chromatography column and eluted with a gradient of 100:0 to 30:70 DCM : (80:20:2 DCM:MeOH:ammonium hydroxide) over 20 min. The appropriate fractions were combined and the solvent removed to provide 0.20 g of the title compound as a white solid (85 %). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=1.1 Hz, 2H), 7.30-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.74 (bs, 1H), 6.64 (s, 1H), 5.91 (q, J=6.4 Hz, 1H), 4.45-4.38 (m, 1H), 3.97 (s, 3H), 2.71-2.61 (m, 2H), 2.47-2.27 (m, 2H), 2.29 (s, 3H), 2.05-1.87 (m, 4H), 1.77 (d, J=6.4 Hz, 3H). MS (ESI): 591 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20]([N:22]3[CH2:24][CH2:23]3)=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:25])[C:11](=[O:26])[CH2:10][N:9]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[C:37]([OH:41])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:25])[C:11](=[O:26])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)=[O:21])([CH3:40])([CH3:39])[CH3:38]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N3CC3)ccc21
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCOC(C)(C)C)ccc21
Reaction time: 0.33 h

Procedure:
2 g (0.0057 M) of N-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1-aziridinecarboxamide in 50 ml of tert.butanol are treated with 3 ml of 25% sulphuric acid. After 20 minutes, the mixture is made alkaline with 10% sodium bicarbonate solution and extracted several times with methylene chloride. The methylene chloride solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 80 g silica gel column using ethyl acetate as the eluting agent and recrystallised from ethyl acetate. There is obtained 1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 177° C.
Reaction SMILES: CN(OC)[C:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)=[O:4].C[Mg]Br.Cl.[CH2:16]1COC[CH2:17]1>CCOCC>[O:7]1[CH:8]=[CH:9][C:5]([C:3](=[O:4])[CH2:16][CH3:17])=[CH:6]1
Reactant: CON(C)C(=O)c1ccoc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 3-(N-methyl-N-methoxycarbamoyl)furan (14 g, 0.09 mol) in 150 ml of THF cooled to -78° C. was added in portions 36.1 ml (0.108 mol) of 3M methylmagnesium bromide in ether and the mixture was allowed to warm to room temperature, and then stirred for 30 min. To the above mixture was added a cold 2N HCl (100 ml) and the aqueous layer was extracted with ether (3×100 ml), the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield a pale-yellow oil. The above oil was chromatographed on silica (methylene chloride/hexane 2:1) to afford 6.95 g (70.2%) of 1-(3-furyl)-1-propanone as a colorless oil which crystallized as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15](Br)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1Br
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of (3E)-6-bromo-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (2.3 g, 6.0 mmol) and morpholine (1.0 mL, 11.4 mmol) in 10 mL of DMF was heated in 96 C bath for 3 hours. The mixture was cooled to room temperature and poured into 200 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:16][CH3:17].C(O)(C(F)(F)F)=O.[CH3:25][N:26]1[CH:30]=[C:29]([C:31]2[C:36]3[N:37]=[C:38](S(C)(=O)=O)[N:39]=[CH:40][C:35]=3[CH:34]=[CH:33][N:32]=2)[CH:28]=[N:27]1>FC(F)(F)CO.CCOC(C)=O>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:38]1[N:39]=[CH:40][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)[C:36]=2[N:37]=1
Reactant: Cn1cc(-c2nccc3cnc(S(C)(=O)=O)nc23)cn1
Reactant: COc1cc(C(=O)N2CC(OC)C2)ccc1N
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Reaction time: 18 h
Yield: 20.4 %

Procedure:
A solution of (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 28, 56 mg, 0.237 mmol), TFA (46 μL, 0.601 mmol) and 8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 35, 35 mg, 0.121 mmol) in 2,2,2-trifluoroethanol (0.6 mL) was heated to reflux for 5 hours and then to 80° C. for 18 hours. The reaction was diluted with EtOAc, quenched with aqueous saturated NaHCO3 and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried, concentrated in vacuo and purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 10% MeOH in EtOAc to afford the title compound (11 mg, 20%). 1H 1HNMR (500 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.17 (s, 1H), 8.64 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.42-7.28 (m, 2H), 4.56 (s, 1H), 4.33-4.20 (m, 3H), 3.89-3.87 (m, 7H), 3.25 (s, 3H).