Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[O:3]=[C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: O=C=NCCCCN=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 3 %

Procedure:
Compound 238 was prepared following the procedure outlined in Example 208 using 1,4-diisocyanatobutane (5.64 mg, 0.402 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 175.1, 58.8 mg, 0.805 mmol). Purification by preparative HPLC gave the title compound (13.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.86 (d, J=8 Hz, 2H), 7.72 (s, 2H), 7.61 (t, 2H), 7.52 (s, 2H), 7.47 (d, J=7 Hz, 2H), 7.18 (s, 5H), 7.78 (s, 2H), 4.77-4.68 (m, 5H), 4.48-4.40 (m, 2H), 3.35-3.28 (m, 2H), 3.56-3.51 (m, 16H), 3.45 (t, J=5 Hz, 5H), 3.35-3.32 (m, 10H), 3.09 (s, 6H), 3.03 (t, J=5 Hz, 3H). MS (m/z): 1145.01 [M+H]+.
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[O:37])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C(OCC)(=O)C>O1CCCC1.O.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>[OH:23][C@@H:21]([C@H:17]1[C:16](=[O:24])[N:15]2[C@@H:18]1[C@@H:19]([CH3:20])[C:13]([S:12][C@@H:10]1[CH2:11][NH:7][C@H:8]([CH2:31][O:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[O:37])[CH2:9]1)=[C:14]2[C:25]([OH:27])=[O:26])[CH3:22]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCNC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.73 g) in a mixture of tetrahydrofuran (34 ml) and water (11 ml) were added triphenylphosphine (0.41 g), dimedone (1.32 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g) successively with stirring at ambient temperature. The mixture was stirred at the same temperature for 3 hours. To the solution were added ethyl acetate (50 ml) and water (30 ml). The aqueous layer was separated and washed 3 times with ethyl acetate (30 ml). This aqueous layer was concentrated in vacuo to remove the organic solvent. The residue was chromatographed on activated charcoal (made by Wako Pure Chemical Industries) (30 ml) eluting in turn with water (90 ml) and 15% aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-1azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Brc1ccc(C2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 115 °C

Procedure:
To a solution of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (440 mg, 1.37 mmol) and 4-(4-bromophenyl)tetrahydro-2H-pyran (300 mg, 1.24 mmol) in toluene (6 mL), ethanol (3 mL), and tetrahydrofuran (3 mL) followed by the addition of 2M potassium carbonate aqueous (3 mL, 6 mmol). Nitrogen was bubbled through the reaction for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium-dichloromethane complex (120 mg, 0.143 mmol) was added and the reaction heated to 115° C. for 16 hours. The reaction was then cooled to room temperature and filtered through a pad of celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified using the Biotage Isolera One (SNAP 50 g silica gel column) and eluting with a gradient of 0-100% ethyl acetate/heptane yielding 360 mg of the title compound as a solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:5])[CH3:4].[H-].[Na+].C[O:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18](OC)=O)[CH:17]=1)=[O:11].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:4][C:3]1[N:5]=[C:18]([C:16]2[CH:17]=[C:12]([C:10]([OH:11])=[O:9])[CH:13]=[N:14][CH:15]=2)[O:1][N:2]=1
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Reactant: CC(N)=NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(-c2cncc(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a suspension of 1-(hydroxyimino)ethylamine (7.4 g) in dry tetrahydrofuran (450 ml) was added sodium hydride (3.7 g, 60% in mineral oil) carefully. The mixture was stirred at room temperature for 15 minutes, and refluxed for 30 minutes. To this mixture was added 3,5-bis(methoxycarbonyl)pyridine (15 g), and the mixture was refluxed for 3 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml) under stirring. The aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylic acid (5.04 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])=O)[CH2:16][CH2:15][S:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].ClC1C=CC=CN=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])=[N:18][C@@H:17]3[CH2:16][CH2:15][S:14][CH2:13][C@@H:12]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2cccc(C(=O)OC)c2)ccc1OC
Agent: Clc1ccccn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)OC)c1)=N[C@@H]1CCSC[C@H]21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 3-{[(3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-yl]carbamoyl}benzoate (2.58 g; compound C11) and 2-chloropyridin (0.68 ml) in toluene (60 ml) is slowly added a solution of POCl3 (1.65 ml) in toluene (6 ml). The reaction mixture is stirred for 12 h at 100° C. The reaction mixture is allowed to come to RT and then quenched by slow addition of water (15 ml). Additional water (30 ml) is added and the pH is adjusted to about 9 by addition of 5 M aqueous solution of sodium hydroxide. The organic phase is separated and the aqueous phase is extracted with toluene (30 ml). The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The resulting residue is purified flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 1/1 (v/v)] to yield the title compound as a solid.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5]1=[O:20].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:26][C:25]=1[S:35]([NH2:38])(=[O:37])=[O:36].CO.C(OCC)C>O1CCOCC1>[CH:17]1([CH2:16][NH:15][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([OH:14])=[C:4]([C:3]3[NH:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[CH:26][C:25]=4[S:35](=[O:37])(=[O:36])[N:38]=3)[C:5]2=[O:20])[CH2:18][CH2:19]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Yield: 15.5 %

Procedure:
A solution of the product of Example 353B (0.090 g, 0.269 mmol, 1 eq.), and the product of Example 425D (0.071 g, 0.269 mmol, 1 eq.), in anhydrous dioxane (5 mL) was heated for 1 hour at 120° C. After cooling the reaction mixture to 25° C., methanol (20 mL) and diethyl ether (20 mL) were added and the precipitated product collected by vacuum filtration to give the title compound (21 mg, 15.5% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.16 (m, 2 H) 0.41 (m, 2 H) 1.07 (m, 1 H) 2.85 (m, 2 H) 3.10 (s, 3 H) 6.44 (m, 1 H) 7.44 (t, J=7.54 Hz, 1 H) 7.62 (m, 2 H) 7.71 (m, 1 H) 7.90 (t, J=7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=6.99 Hz, 1 H) 10.30 (m, 1 H) 14.15 (m, 1 H). MS (ESI+) m/z=504 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH:17]1([C:20]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:2][CH2:3]2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)C2CC2)CC1
Reaction time: 3 h
Yield: 93.2 %

Procedure:
In 35 mL of N,N-dimethylformamide were dissolved benzyl 1-piperazinecarboxylate (5.00 g, 22.7 mmol) and cyclopropanecarboxylic acid (2.54 g, 29.5 mmol), and 1-ethyl-3-(3-(N,N-dimethylamino)propyl)-carbodiimide hydrochloride (6.53 g, 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) and triethylamine (3.60 g, 35.9 mmol) were added thereto at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was mixed with water, and extracted twice with ethyl acetate. The organic layer was sequentially washed with water twice, with a saturated aqueous solution of sodium bicarbonate once and with brine once, and then dried over anhydrous sodium sulfate. The organic layer was passed through a silica gel column (Fuji Silysia, NH Silica gel) and evaporated to give the title compound (6.10 g, 93.1%) as a white amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1.Br[CH2:23][CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[N+:18]([C:17]1[CH:16]=[CH:15][C:14]([O:21][CH2:25][CH:24]=[CH2:23])=[CH:13][CH:12]=1)([O-:20])=[O:19]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
Potassium carbonate (49.7 g, 0.36 mol) was added to an N,N-dimethylformamide (250 ml) solution of p-nitrophenol (25.0 g, 0.18 mol) under nitrogen atmosphere and suspended, and 3-bromopropene (21.7 g, 0.18 mol) was dropwise added thereto. After finishing dropwise adding, the solution was stirred at a room temperature for 5 hours, and then extracting practice with diethyl ether was carried out after adding water to the solution. The organic layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was refined by means of silica gel chromatography (eluent solvent: toluene). Toluene was distilled off under reduced pressure, and then the resulting residue was recrystallized from ethanol to obtain allyl p-nitrophenyl ether (25.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH:6][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CCSCC
Solvent: CO
Product: CCOC(=O)[C@H](CCSCC)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React L-ethionine ethyl ester (3.51 g) and 3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that described in Example 1, Step 1 to give a yellow residue. Chromatograph the yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute with ethyl acetate:hexane 2:18 (16L), then ethyl acetate:hexane 3:17. Repeat chromatography of the fractions using ethyl acetate:hexane as eluant to give Isomer A, a white solid (0.89 g), m.p. 84°-90°, [α]D26 =-60.6° (MeOH) and Isomer B (0.82 g), m.p. 79°-84°, [α]D26 =-0.3° (MeOH).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:9]#[N:10].[K+].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(O)(=O)C>CO>[CH:12]1([NH:15][C:1]2([C:9]#[N:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:13]1
Reactant: O=C1CCCCCC1
Reactant: NC1CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC1(NC2CC2)CCCCCC1
Reaction time: 24 h

Procedure:
5 g (44.57 mmol) of Cycloheptanone and 4.1 g of potassium cyanide were added to a solution of 4.38 ml (62.4 mmol) cyclopropylamine and 3.56 ml (62.4 mmol) of acetic acid in 50 ml MeOH. The reaction-mixture was stirred for 24 h, and then it was concentrated under reduced pressure, taken up in EtOAc and washed with water. The organic layer was concentrated under reduced pressure to give 6.84 g almost pure 1-Cyclopropylamino-cycloheptanecarbonitrile. MS (ESI): 179.3 (M+H)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.O.[C:6]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(OCC)(=O)C>[CH:1]1([NH:4][S:20]([C:16]2[CH:15]=[C:14]([S:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5 ml of cyclopropylamine and 10 ml of water was added to a solution of 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to an oil which crystallized from isopropyl ether to give 839 mg of the titled compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH2:19][OH:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1>O1CCCC1.CC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: OCc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=[Mn]=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C
Reaction time: 10 h
Yield: 85.2 %

Procedure:
[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-methanol 10e (0.96 g, 2.58 mmol) is dissolved in tetrahydrofuran/acetone (1:1, 15 mL), and MnO2 (2.24 g, 25.8 mmol) is added. The reaction mixture is stirred at 50° C. for 10 hours under N2. The reaction mixture is filtered through silica gel and eluted with methylene chloride/methanol (10:1, 1 L). The filtrate is concentrated under reduced pressure to a small volume and then filtered through an Acrodisc syringe filter to remove small amounts of MnO2 that passed through the silica gel. The filtrate is concentrated under reduced pressure and the residue is purified by flash column chromatography (eluting with 20:1 methylene chloride:methanol) to yield 0.81 g (85%) of the pure desired product as a bright yellow solid. MS ESI (+) m/z 368, 370 (M+, Br pattern) detected.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To 4,6-dichloropyrimidine (500.0 mg, 3.36 mmol) and 3-amino-N-methylbenzamide (504 mg, 3.36 mmol) in 2-propanol (5.00 mL) at RT was added N,N-diisopropylethylamine (0.877 mL, 5.03 mmol). The resulting reaction mixture was heated at 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (25 g cartridge, 40 g column, 0 to 100% EtOAc-hexanes then 30-100% 90:10 CH2Cl2-MeOH in CH2Cl2). Fractions with product were combined and concentrated giving 3-(6-chloropyrimidin-4-ylamino)-N-methylbenzamide (815.2 mg).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[CH:8]=[CH:9][CH:10]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-:27].[NH4+]>CCOCC.O1CCCC1>[ClH:27].[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:22]2([OH:26])[CH2:23][CH2:24][CH2:25][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21]2)[CH:10]=[CH:9][CH:8]=1
Reactant: [Cl-]
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: COc1cccc(Br)c1
Agent: II
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Product: Cl
Reaction time: 16 h

Procedure:
9 g of magnesium were activated by sublimation of iodine and were cooled and 20 ml of ether and 2 ml of tetrahydrofuran were added thereto. Then, 2 ml of m-bromoanisole were added thereto under an inert atmosphere and the reaction began. Then, a solution of 50 ml of m-bromoanisole in 200 ml of ether and 20 ml of tetrahydrofuran were added dropwise to the mixture over 2 hours and the mixture was refluxed for one hour and allowed to stand for 16 hours. 120 ml of the solution were cooled to 5° to 10° C. while adding a solution of 20 g of N-benzyl-3-piperidone in 100 ml of tetrahydrofuran dropwise under an inert atmosphere. The mixture was stirred for 3 hours and was then cooled in an ice bath. 200 ml of aqueous saturated ammonium chloride solution were added dropwise to the mixture at 5° to 20° C. and the mixture was vacuum filtered. The decanted aqueous phase was extracted with ethyl acetate and the ethyl acetate extract was extracted with 2 N hydrochloric acid. The aqueous extract was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 30 g of residue were dissolved in ethyl acetate and a solution of hydrogen chloride gas in ethyl acetate was added thereto until the pH was acidic. Crystallization was induced and the mixture was vacuum filtered to obtain 3-(3-methoxyphenyl)-1-benzyl-piperidine-3-ol hydrochloride melting at 210° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.C(N(CC)CC)C.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:48](=[O:51])[CH2:49][CH3:50])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (80.0 mg, 0.146 mmol) was stirred in Methylene chloride (1.60 mL, 25.0 mmol) with Triethylamine (30.6 μL, 0.219 mmol) at room temperature. Propanoyl chloride (12.7 μL, 0.146 mmol) was then added quickly under nitrogen. The reaction was complete after stirring over night. The reaction mixture was washed with bicarb and extracted with XS DCM. The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on an ISCO flash system (0-10% MeOH:DCM). The desired fractions were concentrated and the product was obtained as a foam from a small amount of DCM (35 mg, 40%). mp: 40° C. softened, 60-70 glass, MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.25 (m, 1H), 6.67 (s, 1H), 4.25 (t, J=6 Hz, 2H), 3.89 (s, 3H), 2.87 (m, 2H), 2.83 (t, J=6 Hz, 2H), 2.76-2.72 (m, 12H), 2.36 (t, J=7.5 Hz, 2H), 1.17 (t, J=7.5, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[C:25](NC3C=CC=C(N)C=3)[N:24]=[CH:23][CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:24][C:23]3[CH:22]=[C:21]([NH:26][C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([N:36]([CH3:46])[CH3:35])=[CH:38][CH:39]=4)[CH:11]=[CH:2][CH:3]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(Nc2nccc(-c3cccc4c3oc3ccccc34)n2)c1
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)Nc2cccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)c2)cc1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidinyl)-benzene-1,3-diamine trifluoroacetate (compound A2) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 4-dimethylaminobenzoyl chloride (222 mg, 1.21 mmol) portion wise. After 2 days at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.