Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)o1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2ccc(Cl)c(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.02 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 158-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[ClH:36]>CO.O1CCOCC1>[ClH:36].[Br:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCNCC2)ccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Bromo-5-(4-[{1,1-dimethylethyl}oxycarbonyl]-piperazin-1-yl)methyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 65b, 0.40 g) was dissolved in methanol (15 ml), and 4N HCl in dioxane (3 ml) added. The mixture was stirred at room temperature for 14 h. The solvent was removed under vacuum and the resulting solid was triturated with ether to afford the title compound as a white powder (0.23 g).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.CN([CH:11]=[O:12])C>>[C:11]1(=[O:12])[O:12][C:11](=[O:12])[C:7]2=[CH:6][CH:7]=[CH:6][CH:7]=[C:6]2[CH2:11]1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Product: O=C1Cc2ccccc2C(=O)O1
Temperature: 80 °C

Procedure:
A solution of homophthalic anhydride (324 mg, 2 mmoles) and triethylamine (0.021 ml, 0.15 mmoles) is prepared in DMF (5 ml) and added to each packet. After heating at 80° C. for 16 hrs the packets are then washed with DMF (3×30 ml) and DCM (3×30 ml).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=O)[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH3:50])[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[CH:42]=2)=[N:37]1>>[Cl:49][C:43]1[CH:42]=[C:41]([C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:34]([NH:33][C:30]([C:28]3[O:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:24]=4)[N:29]=3)=[O:32])[CH3:50])[N:37]=2)[CH:48]=[CH:47][C:44]=1[C:45]#[N:46]
Reactant: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.211 g, 0.499 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.1 g, 0.384 mmol). The product was purified by flash chromatography. LC-MS: [M+1]=666.142.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18]Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
The product from step (vii) (0.15 g) was dissolved in DMSO (2 mL) and pyrrolidine (0.18 g) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered through a filter disc and purified via RP-prep-HPLC to give title compound (0.044 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=C[CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1[N:32]=C(CC)C(NC2C3C(=NC=CC=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:25](=[N:32][CH:19]=[CH:20][CH:21]=3)[CH2:24][CH2:23]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCc3ncccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2ncccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting N-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.50, 7.73, 7.51, 7.36-7.28, 7.17, 5.88, 4.67, 3.26-3.08, 2.86, 2.70, 2.51, 2.05-1.96, 1.29, 1.12; HRMS (FAB) calcd for C22H22Cl2N4+H 413.1299, found 413.1286.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.[CH2:15]([S:22][CH2:23][C@@H:24]1[CH2:28][C@@H:27]([S:29]CC2C=CC(OC)=CC=2)[CH2:26][N:25]1[S:39]([CH3:42])(=[O:41])=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:15]([S:22][CH2:23][C@H:24]1[N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:26][C@H:27]([SH:29])[CH2:28]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CSCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1CSCc1ccccc1
Temperature: 80 °C
Yield: 20.5 %

Procedure:
(TFA/triethylsilane for not labile methoxy-benzylsulfanyl, Method 2): 100 mg (0.23 mmol) of (2S,4R)-2-benzylsulfanylmethyl-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine was dissolved in 8.2 ml TFA and treated at 0° C. with 0.35 ml (2.38 mmol) triethylsilane. The reaction was warmed up over night, heated 2.5 min at 80° C. and evaporated. Flash silica gel column (CH2Cl2/EtOAc 99:1) gave 15 mg (21%)of (3R,5S)-5-benzylsulfanylmethyl-1-methanesulfonyl-pyrrolidine-3-thiol, mp 101.5–103.5° C., MS: 318 (MH+).
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[ClH:22].[CH2:23]([O:25][C:26](=[O:33])[C@@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH2:28])[CH3:24]>>[ClH:22].[ClH:22].[CH2:23]([O:25][C:26](=[O:33])[C@@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH:28][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1)=[O:15])[CH3:24]
Reactant: CCOC(=O)[C@H](N)CCSC
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: Cl
Product: CCOC(=O)[C@@H](CCSC)NC(=O)C1CSC(c2cccnc2)N1

Procedure:
N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and D-methionine ethyl ester hydrochloride were used as the starting materials and treated in the same manner as in Example 4 to give [2-(3-pyridyl)thiazolidine-4-carbonyl]-D-methionine ethyl ester dihydrochloride. Melting point 94°-96° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:21][C:22]1[C:26]([C:2]2[C:11]3[O:10][CH2:9][CH:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]4)[N:7]4[C:18](=[O:20])[NH:19][C:5]([C:6]=34)=[CH:4][CH:3]=2)=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(C1CCCCN1)CO3
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3C1CCCCN1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The 7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.025 g, 0.074 mmol) of Step 2 was combined with (3,5-dimethylisoxazol-4-yl)boronic acid (0.016 g, 0.11 mmol) in 1,4-dioxane (3.0 mL) with potassium carbonate (0.02 g, 0.15 mmol) in water (0.38 mL) and was degassed with nitrogen. The catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.006 g, 0.007 mmol) was added and the reaction was heated in a sealed tube to 100° C. After stirring for 2 h the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark oil. The product was purified by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as two fractions.
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:24][C:25]1[CH:30]=[C:29](/[C:31](/[C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[C:40]([O:46][CH3:47])[N:39]=2)=[CH:32]\[CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=[CH:27][C:26]=1[S:48][CH2:49][CH2:50][CH2:51][OH:52]>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:52][CH2:51][CH2:50][CH2:49][S:48][C:26]2[CH:27]=[CH:28][C:29](/[C:31](/[C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[C:40]([O:46][CH3:47])[N:39]=3)=[CH:32]\[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:30][C:25]=2[Cl:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCO)c(Cl)c2)nc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Triethylamine (87 μL), trimethylamine hydrochloride (20 mg) and 4-methylbenzenesulfonyl chloride (60 mg) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol (95 mg) in chloroform (2 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) as a yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@:18]3([CH3:29])[O:22][C:21]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]4[CH2:19]3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[CH3:29][C@@:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[C:39](=[O:41])[CH3:40])[CH2:12][CH2:13]2)[O:22][C:21]2=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]2[CH2:19]1
Reactant: C[C@]1(CN2CCC(Nc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N(c1ccc(OC(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
(S)-2-[4-(4-Trifluoromethoxyphenyl)aminopiperidin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 282 (153 mg, 0.35 mmol) was dissolved in methylene chloride (5 ml). To the solution, triethylamine (30 μl) and acetyl chloride (30 μl) were added followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-(4-trifluoromethoxyphenyl)acetamide (82 mg, yield 49%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1.0 g, 1.73 mmol) in CH2Cl2 (50 mL) was added 1-methylpiperazine (0.40 mL, 3.6 mmol). The resulting mixture was allowed to stir at room temperature overnight, then diluted with CH2Cl2 (30 mL), the organic layer was washed with 9% aq. Na2CO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.C(O)(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(N)cn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-amino-2-methoxypyridine (1.00 g, 8.06 mmol) in dichloromethane (20.0 mL) was treated with benzaldehyde (0.080 mL, 8.06 mmol) followed by stirring at ambient temperature for 20 min. The mixture was then treated with sodium cyanoborohydride (1.79 g, 8.46 mmol) followed by acetic acid (0.460 mL, 8.06) and continued stirring for 2 h. The solution was treated with water and saturated sodium hydrogen carbonate, and then extracted twice with dichloromethane. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was swirled in hexanes, and a solid was filtered. The filtrate was concentrated and the title compound was obtained as a light pink solid (0.340 g, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=2.5 Hz, 1H), 7.28-7.41 (m, 5H), 7.01 (dd, J=8.8, 3.0 Hz, 1H), 6.62 (d, J=9.3 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H). MS(ES+) m/e 215 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=S)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].OO.C([O-])(O)=O.[Na+]>Cl>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc(=S)[nH]c1C
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Product: CCOC(=O)c1scnc1C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A solution of ethyl 4-methyl-2-thioxo-2,3-dihydro-1,3-thiazole-5-carboxylate (2.51 g) in HCl (37%, 8 mL) was warmed to 50° C., H2O2 (30%, 4.2 g) was added dropwise over 20 min and the reaction mixture was stirred for 1 h and allowed to reach room temperature. The mixture was then treated with NaHCO3 up to a slightly basic pH and extracted twice with ether (2×20 mL), the organic phase separated and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with cyclohexane : ethyl acetate from 1:0 to 7:3) to give the title compound (0.5 g). MS (m/z): 172 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for the example 4 from 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (100 mg, 0.353 mmol) and 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (129 mg, 0.565 mmol), wherein the reaction stir time was 12 h. The product was collected as a white solid (130 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.17-7.26 (m, 6H), 5.81 (s, 1H), 5.04 (m, 2H), 4.42 (s, 2H), 3.96 (s, 2H), 2.10 (s, 3H), 1.45 (d, 6H); MS (ES) [M+H]+ 495.0.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35]C)=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:9])[CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([OH:35])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:20])=[O:21])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CC[C@@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 80 °C
Yield: 49.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-ylcarbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 195, 0.215 g) and lithium hydroxide monohydrate (0.170 g) was suspended in dioxane (5 mL) and water (5 mL) and the mixture was stirred and heated at 80° C. for 21 hours. The temperature was raised to 100° C. and the mixture was stirred and heated at that temperature for 2.5 hours. Further lithium hydroxide monohydrate (0.05 g) was added and the mixture was stirred and heated at 100° C. for 2 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-ylcarbonyl)-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.103 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28]>CC(C)=O.O>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[O:20][CH2:27][CH3:28]
Reactant: CCI
Reactant: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(4-bromo-3-hydroxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-106, 1.61 g, 4.77 mmol), potassium carbonate (1.97 g, 14.31 mmol) and ethyl iodide (3.8 mL, 47.7 mmol) in acetone (50 mL) was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow oil. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.26 g, 6.09 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (9.39 mL, 122 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was partitioned between methylene chloride (100 mL) and 1N sodium hydroxide (100 mL). The alkaline phase was extracted with methylene chloride (2×100 mL). The combined organic phase was dried over sodium sulfate and concentrated to give 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 271.07, 272.96.