Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[O:10][C:11]([CH3:15])([CH3:14])[CH2:12]Cl)=[C:6]([NH2:17])[N:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)[N:3]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]([N:8]2[CH2:12][C:11]([CH3:15])([CH3:14])[O:10][C:9]2=[O:16])=[C:6]([NH2:17])[N:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)[N:3]=1
Reactant: CC(C)(CCl)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CN(c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2N)C(=O)O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
500 mg (1.033 mmol) of the compound prepared in example 7A were dissolved in tetrahydrofuran (10 ml), and 1.033 ml of a 1M solution of bis(trimethylsilyl)sodium amide solution in tetrahydrofuran were added at 0° C. After stirring at 0° C. for 5 min, the reaction was stopped by addition of saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 329 mg of the title compound were obtained (71% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[C@@H:11]3[C@H:16]([CH2:17][CH2:18][C:9]=2[CH:8]=[CH:7][CH:6]=1)[N:15]([C:19]([C:21]1[CH:29]=[CH:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20])[CH2:14][CH2:13][CH2:12]3)=O>C(Cl)Cl.CO>[NH:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]([N:15]3[C@@H:16]4[C@@H:11]([C:10]5[C:5]([CH2:3][OH:2])=[CH:6][CH:7]=[CH:8][C:9]=5[CH2:18][CH2:17]4)[CH2:12][CH2:13][CH2:14]3)=[O:20])=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3c(CO)cccc3CC[C@@H]21
Yield: 46 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 34. Yield: 46% of theory; TLC: rf=0.27 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C[Si]([C:13]#[N:14])(C)C.N12CCCN=C1CCCCC2>C1COCC1>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1)#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88–89° C. Anal. Calc'd. for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.17; H, 5.12; N, 23.44.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:32][CH2:33][CH:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CS(=O)(=O)NC1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CS(=O)(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-piperidin-4-yl-methanesulfonamide following General Procedure B.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20](O)=[O:21].[F:23][C@@H:24]1[CH2:28][NH:27][C@H:26]([CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([N:27]1[CH2:28][C@@H:24]([F:23])[CH2:25][C@H:26]1[CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=[O:21]
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2F)cc1
Temperature: 0 °C
Yield: 91.5 %

Procedure:
In DMF (5 ml), 7-fluoro-2-(2-methylphenylamino)-6-benzoxazolylacetic acid (300 mg, 1.0 mmol), methyl 4-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)benzoate (253 mg, 1.0 mmol), EDC•HCl (288 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol) and triethylamine (0.70 ml, 5.0 mmol) were stirred at room temperature for 14 hours. After the reaction mixture was poured in ice water (20 ml), the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (490 mg, 92%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[S:56][S:55][C:54](=[S:57])[CH:53]=2)=[CH:48][CH:47]=1>CN(C)C=O.C(OCC)(=O)C>[S:57]=[C:54]1[S:55][S:56][C:52]([C:49]2[CH:48]=[CH:47][C:46]([O:9][C:8](=[O:10])[CH2:7][C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[NH:11][C:12]3[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:18])=[CH:51][CH:50]=2)=[CH:53]1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc(-c2cc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To the solution of 1 (diclofenac, 890 mg, 3.0 mmol) in 50 mL of N,N-dimethylformamide, hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 678 mg, 3 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure and the oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which [2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (3) was obtained (1.1 g, 74% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:18]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[N:19]=1.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCCCCCCCn1ccnc1
Agent: Cl
Agent: I
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.1 g of 8-(1H-imidazol-1-yl)octanamine, 400 ml of ethanol, and 3.2 g of 2-(methylthio)benz[cd]indole hydroiodide was reacted as described in Example 19, giving the base derivative which was then treated with hydrochloric acid giving 1.3 g of the desired hydrochloride salt, mp 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1n[nH]c2cc(Cl)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Example 40, Step 1; 630 mg, 1.479 mmol) was dissolved in TFA (4 mL) and triethylsilane (0.354 mL, 2.219 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 was added and the products extracted into EtOAc followed by 3:1 chloroform/IPA. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was titrated with ether to afford 6-chloro-3-methoxy-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C7H6ClN3O [M+1]+ 184. found 184.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:22][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:35]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 0.075 g (0.25 mmol) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in methylene chloride (5 mL) is added 0.050 mL (0.30 mmol) of triethylamine followed by 0.044 g (0.25 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then purified by preparative reverse phase HPLC to give 0.033 g (30%) of the title compound (3) as a white solid. [M+H]+=441.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1)[CH3:20])=[CH:7]2.O.[OH-].[NH4+:31]>O1CCOCC1.[Cl-].[Na+].O>[NH2:31][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[CH:27]=1
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1cc(N)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A heavy-wall glass tube with stir bar and FEP-encapsulated-silicone o-ring seal was charged with 77 (ca. 300 mg, 0.73 mmol) in 1,4-dioxane (12 mL) and concentrated ammonium hydroxide solution (10 mL), then sealed tightly and heated at 120° C. After 16 h, more ammonium hydroxide (6 mL) was added and heating continued at 150° C. during 6 h, then 160° C. during 24 h. A third portion of ammonium hydroxide (8 mL) was added and heating continued at 150° C. during 3 days. The reaction mixture was poured into a mixture of water and brine (35 mL each), stirred about 1 h at 0° C., and the resulting precipitate collected by filtration and washed with ice-water. This material was dried in vacuo to give (S)-3-(1-(6-aminopyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 78. ESI-MS m/z: 392.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([CH2:43][C:44]([NH2:46])=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 647.2 [(M+H)+]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@@H]1CCNC1

Procedure:
To (3R)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-pyrrolidin-3-yl)acetamide. (45 mg, 0.094 mmol)
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of NaH (60% in oil, 43.6 g, 1.09 mol) in DMF (900 mL) is carefully added crude 2-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol (139.5 g) in DMF (300 mL) at 0-5° C., and the mixture is stirred for 30 min at the same temperature. To the mixture is added dropwise benzyl bromide (129.6 mL, 1.09 mol) at 0-5° C., and stirring is continued for 1 hour at the same temperature. After addition of H2O (1000 mL), the mixture is extracted with EtOAc-Hexane (3:1, 1200 mL). The water layer is extracted with EtOAc-Hexane (3:1, 1200 mL×2), and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 8-[2-(benzyloxy)ethyl]-1,4-dioxaspiro[4.5]decane. The crude product is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[C:17]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:22]([NH:21][C:17]1[C:16]([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=2[Cl:1])=[N:20][O:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)Nc1nonc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
173 mg (0.5 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 191 mg (0.505 mmol) of N-(4-amino-1,2,5-oxadiazol-3-yl)acetamide are dissolved in 5 ml of dichloroethane at RT and treated with 0.071 ml (0.5 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 483 mg (0.76 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 24 h at RT and subsequently filtered through a glass frit. The residue is washed twice using in each case 1 ml of CH2Cl2. The filtrate is passed over a silica-gel-filled SPE cartridge and eluted twice using in each case 5 ml of a mixture of ethyl acetate/methyl tert-butyl ester (1:1). The organic phase is dried over Na2SO4 and evaporated. The residue is purified by preparative HPLC using acetonitrile/water. Yield 16 mg (9%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:11]([N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[CH:10][C:9]([NH2:19])=[C:8]([NH2:20])[CH:7]=1)(=[O:5])=[O:4].[C:22](O)(=[O:26])[C:23](O)=[O:24].N>Cl>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:13]=[CH:14][C:15](=[O:18])[CH:16]=[CH:17]1)[NH:19][C:23](=[O:24])[C:22](=[O:26])[NH:20]2)(=[O:5])=[O:4]
Reactant: O=C(O)C(=O)O
Reactant: CN(C)S(=O)(=O)c1cc(N)c(N)cc1-n1ccc(=O)cc1
Agent: Cl
Agent: N
Product: CN(C)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1-n1ccc(=O)cc1
Yield: 34.2 %

Procedure:
First, a mixture containing 500 mg of 4-dimethylsulfamoyl-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, 438 mg of oxalic acid, and 10 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 3 hours. The mixture was cooled and made basic with aqueous ammonia. Precipitated crystals were filtered. Then, 534 mg of the crude crystals thus obtained were further recrystallized with dimethylformaldehyde and water to give 201 mg of 6-dimethylsulfamoyl-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].[Br:22][CH2:23][CH2:24]Br>CN(C)C=O>[Br:22][CH2:23][CH2:24][N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7](=[O:13])[C:8]1=[O:12]
Reactant: BrCCBr
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCBr)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 100 ml of N,N-dimethylformamide was suspended 10 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 1.67 g of sodium hydride (60%, oil) was added to the suspension, followed by stirring at 50° C. for 1 hour. Then, the reaction mixture was cooled to room temperature, after which 16.5 ml of 1,2-dibromoethane was added thereto and the resulting mixture was stirred at the same temperature for 4 hours. After the solvent was distilled off under reduced pressure, a mixed solvent of 100 ml of ethyl acetate and 60 ml of water was added to the residue and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was washed with 20 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=30:1) to obtain 6.1 g of 1-(2-bromoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Br:18])=[CH:20][CH:21]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid ethyl ester (1.6 g) synthesized in Example 155-1 and 4-bromobenzylbromide (1.7 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.72 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 3:1) to give the title compound (1.3 g) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[CH:25]([O:28][C:29](Cl)=[O:30])([CH3:27])[CH3:26]>N1C=CC=CC=1>[CH:25]([O:28][C:29](=[O:30])[NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7]=2[F:17])=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)=[CH:23][CH:22]=1)([CH3:27])[CH3:26]
Reactant: CCOc1ccc2c(F)c(-c3ccc(N)cc3)n(CC3CC3)c2c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1ccc2c(F)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
A mixture of 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl amine (30 mg, 0.093 mmol), pyridine (300 μL), and isopropylchloroformate (1 M in toluene, 110 μL, 0.11 mmol) was stirred at room temperature for 90 minutes. The residue was extracted with a mixture of EtOAc and aqueous HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2/Hex, 1:1) to provide [4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (35 mg, 92%) as a white solid.