Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[C:15]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][S:25][CH:26]([CH3:28])[CH3:27])=O)[CH2:18][C:16]=3[S:17][C:13]=2[N:12]2[C:29]([CH3:32])=[N:30][N:31]=[C:11]2[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[C:15]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][S:25][CH:26]([CH3:28])[CH3:27])=[S:42])[CH2:18][C:16]=3[S:17][C:13]=2[N:12]2[C:29]([CH3:32])=[N:30][N:31]=[C:11]2[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=O)CSC(C)C)C3
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)CSC(C)C)C3

Procedure:
Into the same reactor as in example 1, were poured, under nitrogen circulation, 300 ml of toluene, 12.2 g (0.025 mol) of the product of example 1 and 4.75 g (0.0117 mol) of Lawesson's reagent. The reaction mixture was slowly warmed over two hours to reflux temperature and reflux was maintained for two hours. After evaporation to dryness and treatment with dichloromethane, the solution was passed on a silica gel column, eluting with dichloromethane:methanol 95:5 by volume. After evaporation to dryness of the resulting solution, the residue was recrystallized from methanol. Yield 10.2 g (82%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:30]3[CH2:29][CH2:28][CH:27]([CH2:26][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:32][CH2:31]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-pyrrolidin-1-ylmethyl-piperidine, dihydrochloride salt using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-pyrrolidin-1-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (63% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 331 as an off white solid (84% yield). NMR (CDCl3, 400 MHz), 1.28-1.36 (2H, m), 1.48-1.52 (1H, m), 1.77-1.82 (6H, m), 2.10 (2H, t, J=11.0), 2.34 (2H, d, J=7.0), 2.44-2.49 (4H, m), 2.99 (2H, d, J 11.0), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=495
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]([C:18]1[O:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:23][C:20]2[O:19][C:18]([C:16]([OH:17])=[O:15])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1ccc(CCl)o1
Product: O=C(O)c1ccc(COc2cccc(-c3ccccc3)c2)o1

Procedure:
5-(Biphenyl-3-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 67 mg. Mass spectrum (ES) MH+=295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.C1CCN2C(=NCCC2)CC1.[CH2:42]([O:49][C:50]1[N:51]=[N:52][C:53]([C:64]#[CH:65])=[CH:54][C:55]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:42]([O:49][C:50]1[N:51]=[N:52][C:53]([C:64]#[C:65][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:54][C:55]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Clc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 1-chloro-3-iodobenzene (0.862 g, 3.62 mmol) in dry tetrahydrofuran (11 ml) was added copper(I) iodide (0.063 g, 0.33 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.115 g, 0.16 mmol) and 1,8-diazabicycloundec-7-ene and (DBU; 2.97 ml, 19.72 mmol). The reaction was then purged and evacuated with nitrogen several times before 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5; 1.04 g, 3.29 mmol) was added. The reaction vessel was sealed and heated to 80° C. for 1 hour. Upon cooling, the resultant mixture was partitioned between ethyl acetate and water. The combined organic portions were washed with water (×2) and brine, dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-20% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-((3-chlorophenyl)ethynyl)pyridazine as a yellow solid (yield=30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:8])[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (7-formyl-chroman-4-yl)-methyl-carbamic acid tert-butyl ester (554 mg, 1.90 mmol, 1.0 eq), piperidine (Aldrich, 195 mg, 2.28 mmol, 1.2 eq), NaBH(OAc)3 (Aldrich, 805 mg, 3.8 mmol, 2.0 eq) and glacial HOAc (J. T. Baker, 114 mg, 1.90 mmol, 1.0 eq) in ClCH2—CH2Cl (8 mL) was stirred at RT for 4 h. The reaction was quenched with saturated Na2CO3 (50 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-5% MeOH—CH2Cl2) afforded the title compound as colorless sticky solid. MS (ESI, pos. ion) m/z: 361 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2

Procedure:
To a solution of 1,2,3,4-tetrahydoquinoline (6.5 g, 0.049 mol) in conc. Sulfuric acid (118 mL) at 0° C. was added a solution of con. nitric acid (4.9 mL) in conc. Sulfuric acid (12 mL) drop-wise over 3 hours so as to maintain the temperatute <5° C. The reaction mixture was then poured onto crushed ice and neutralized with solid potassium carbonate. The mixture was extracted with EtOAc (2×500 mL), the combined organic extracts were washed with water, dried and concentrated to give the crude product which was purified by column chromatography on silica-gel using EtOAc/hexane as eluent to obtain the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][Mg]Cl.[I:12][C:13]1[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][CH:14]=1>>[I:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[CH:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: COc1cccc(C[Mg]Cl)c1
Product: COc1cccc(CC(C(=O)c2ccc(I)cc2)c2cccc(OC)c2)c1

Procedure:
The title compound was prepared from (3-methoxybenzyl)magnesium chloride and 4-iodo-N-methoxy-N-methylbenzamide following the procedure outlined for Intermediate 1. 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, 2H), 7.77 (d, 2H), 7.17 (t, 1H), 7.10 (t, 1H), 6.88-6.83 (m, 2H), 6.77-6.65 (m, 4H), 5.17 (t, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38 (dd, 1H), 2.96 (dd, 1H).
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32]([NH:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
To a mixture of ethyl 2-cyano-2-hydroxyiminoacetate (100 g, 0.704 mol) and water (600 ml), were added a saturated aqueous solution of sodium bicarbonate (200 ml) and sodium hydrosulfite (340 g, 1.96 mol) under ice-cooling, and then benzyloxycarbonyl chloride (144 g, 0.848 mol) was added dropwise under ice-cooling. After the addition was completed, the reaction solution was stirred at 20-30° C. for about 4 hours. Completion of the reaction was confirmed using TLC shown below, precipitated crystals were collected by filtration and washed with sprayed water (50 ml×3). The obtained crystals were recrystallized from ethanol (600 ml), filtered and washed with sprayed ethanol (50 ml×3), dried in airflow at 40° C. to give ethyl 2-benzyloxycarbonylamino-2-cyanoacetate (118.7 g, yield 64.2%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.CN([CH:32]=[O:33])C>C1COCC1.O>[CH3:11][N:9]([CH3:10])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:7]=1[CH:32]=[O:33]
Reactant: CN(C)CCOc1cccc(N(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cccc(N(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of Compound 71 (2.8 g, 13.5 mmol) in THF (10 mL) was added TMEDA (1.88 g, 16.2 mmol) followed by n-BuLi (2.5 M solution in hexane, 6.5 mL, 16.2 mmol). The mixture was stirred for 30 min at room temperature then DMF (1.48 g, 20.25 mmol) was added and the solution stirred for 3 h at room temperature. The reaction was then diluted with water (20 mL), and the product was extracted with EtOAc (3×50 mL). The organic layers were combined and washed with brine, and dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. After silica gel chromatography, the product (Compound 72) was obtained as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:35]1[C:40](=[O:41])[N:39]([O:42][C:43]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](ON2C(=O)CCC2=O)=[O:52])=[O:44])[C:37](=[O:38])[CH2:36]1>CN(C=O)C>[C:10]([O:9][C:7](=[O:8])[C@@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C:43]([O:42][N:39]1[C:40](=[O:41])[CH2:35][CH2:36][C:37]1=[O:38])=[O:44])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (0.488 g, 1.0 mmol) in DMF (20 mL) was added dropwise to a solution of suberic acid bis(N-hydroxysuccinimide ester) (1.47 g, 4.0 mmol) in DMF (80 mL) via a syringe pump. After 2 h, the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM to give (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.54 g, 73%). MS (ESI), 741.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[Br:13]Br>CC(O)=O.C(OCC)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:13])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: BrBr
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1cc(Br)c(Cl)cc1N
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of 2-Amino-4-chloro-benzoic acid methyl ester (1.85 g, 10.0 mmole) in HOAc (20.0 ml) was injected bromine (0.512 ml, 10.0 mmole) dropwise. The reaction was stirred at room temperature for an hour. The mixture was diluted with ethyl ether (200 ml) and then the solvents were decanted. The residue was partitioned between ethyl acetate (200 ml) and 0.100N NaOH(aq) (200 ml). After separated the two layers, the organic layer was dried over Na2SO4, filtered and concentrated to provide the crude product (2.08 g, 78%), which was used directly for the next step without further purification. MS (ES+): 264, 266 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:5]([S:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21].I([O-])(=O)(=O)=[O:25].[Na+].O>CO>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=2)[C:5]([S:15]([CH:16]([CH3:17])[CH3:18])=[O:25])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)C(=O)c1nc(SC(C)C)n(-c2ccc(CC)cc2)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)c1nc(S(=O)C(C)C)n(-c2ccc(CC)cc2)c1Cl
Yield: 41.4 %

Procedure:
A mixture of 3.0 g (8.6 mmol) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylthio)-imidazol-4-yl]-2-methyl-2-propen-1-one and 2.3 g (11 mmol) of sodium metaperiodate was heated at 50° C. for 3 hours in 30 ml of 90% aqueous methanol. The mixture was cooled and poured into water. Extraction with dichloromethane yielded an oil which was purified by flash chromatography on silica (20% ethyl acetate in petroleum ether) to obtain 1.3 g (41%) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one as cream-colored crystals melting at 83°-4° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[CH2:15][CH2:16]O)#[N:2].[Br:18]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>C(OCC)C>[Br:18][CH2:16][CH2:15][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(=O)cc(CCO)c2cc(C#N)ccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(=O)cc(CCBr)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
0.24 g (1.05 mmol) of 6- cyano-4-(2-hydroxyethyl)-1-methyl-2(1H)-quinolone is added in small amounts to 0.48 g (1.14 mmol) of dibromotriphenylphosphorane in 14 ml of dichdoromethane at room temperature. After 75 minutes of stirring at room temperature, the reaction medium is poured into 200 ml of dichloromethane and the mixture is washed with water. The organic phase is dried over sodium sulphate, filtered and condensed under vacuum. The white residue is ground in diethylether. The solid obtained is taken up in a minimum of dichloromethane, the mixture is filtered rapidly through a layer of silica, eluting with ether, and the filtrate is evaporated.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1.OS(O)(=O)=O.[OH-].[Na+].[C:24](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:24][O:15][C:14]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid (160 g, 0.73 mol) was dissolved in 300 mL of toluene and 550 mL of methanol. To the solution was added 9 mL of conc H2SO4 and the solution was heated to reflux overnight. The solution was cooled in an ice bath and neutralized to pH 5 with 25% NaOH, followed by adding 50 mL of saturated sodium bicarbonate to bring the solution to pH 7. The methanol was removed on a rotary evaporator and the residue was diluted with 500 mL of water and extracted with methylene chloride. The combined extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded 132 g of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester as an oil which was >95% pure by NMR. 1H NMR (CDCl3) δ 2.0-2.6 (m,4H,CH2 's), 3.68 (s,3 H,CH3), 3.95 (dd, 1 H,J=4,9 Hz, H-4), 4.02 and 5.03 (AB, 2 H,Jgem =16 Hz, CH2Ph), 7.2-7.4 (m, 5 H, arom).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=N[C:46]([CH3:49])=[CH:47][CH:48]=1)[CH2:4][CH2:3]2.BrC1C=C[C:54]([S:57]C)=CN=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][C:46]([S:57][CH3:54])=[CH:49][N:44]=1)[CH2:4][CH2:3]2
Reactant: CSc1ccc(Br)nc1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(SC)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 5.9 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-5-(methylthio)pyridine (0.020 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (5.2 mg, 5.9% yield) bis TFA salt. LCMS: m/e 696.5 (M+H)+, 2.34 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.03 (d, J=1.8 Hz, 1H), 7.93-7.88 (m, J=8.2 Hz, 2H), 7.61-7.57 (m, 1H), 7.21-7.14 (m, J=8.2 Hz, 2H), 6.71 (d, J=8.9 Hz, 1H), 5.27 (dd, J=6.1, 1.5 Hz, 1H), 4.87 (s, 1H), 4.75 (br. s., 1H), 4.72 (br. s., 1H), 3.80-3.72 (m, 1H), 3.72-3.63 (m, 1H), 3.18-3.09 (m, 1H), 2.72-2.64 (m, 1H), 2.39 (s, 3H), 2.11 (dd, J=17.1, 6.4 Hz, 1H), 2.08-2.01 (m, 1H), 2.00-1.90 (m, 3H), 1.90-1.74 (m, 3H), 1.72 (s, 3H), 1.71-1.66 (m, 2H), 1.65-1.44 (m, 7H), 1.44-1.33 (m, 3H), 1.33-1.12 (m, 7H), 1.04 (s, 3H), 0.97 (s, 3H), 0.91 (br. s., 3H), 0.91 (br. s., 3H), 0.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:23][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]3)[CH2:21]2)=[O:18])=[N:3]1.CC[N:35]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:21][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:35])=[O:31])[CH2:26][CH2:25]3)[CH2:23]2)=[O:18])=[N:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(N)=O)CC3)C2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexane carboxylic acid (as prepared in the previous step, 100 mg, 0.22 mmol), EDCI (Aldrich, 65 mg, 0.33 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol) and ammonia in THF (1N, Aldrich, 0.5 mL) in DCM (5 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography using DCM: 7N NH3 in MeOH (10:1) as eluent to give the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([O:19][C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:21]=2)=[CH:17][C:16]=1[F:40].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:40][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:15]=1[NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[S:13])[O:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[CH:21]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)c(F)c3)ncn2)CC1
Reaction time: 4 h
Yield: 10 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.4 ml) to a solution of crude 3-[6-(4-amino-3-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea and (+)-10-camphorsulfonic acid (86.2 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and diethyl ether (2.0 ml) was added to the resultant residue to precipitate crystals. The crystals were filtered and then subjected to aeration drying to provide the title compound (21.0 mg, 10%) as white crystals.