Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@H:9]([NH:29][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:10]([NH:12][C@H:13]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:14][C:15](O)=[O:16])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]1([CH2:7][CH2:8][C@H:9]([NH:29][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:10](=[O:11])[NH:12][C@H:13]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:14][CH2:15][OH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)O)CN2CCc3cc(F)ccc32)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CCO)CN2CCc3cc(F)ccc32)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 51.6 %

Procedure:
A sample of the title compound of example 47 (114 mg, 0.21 mmol) in THF (5 mL) was cooled in an ice/water bath and treated with triethylamine (21 mg, 0.21 mmol) followed by isobutyl chloroformate. After stirring for 25 minutes, the solution was transferred to a precooled (ice/water bath) stirring solution of excess NaBH4 in water (5 mL). After stirring for 1 hour, the solution was quenched by addition of excess 1 M HCl at 0° C. The reaction was diluted with ethyl acetate and extracted with 1 M NaOH solution. The organics were dried over MgSO4 and the solvent was removed. The residue was purified on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to afford 57 mg (51%) of the title material as a solid; 1H NMR (CDCl3, 400 MHz) δ 0.65-0.82 (m, 2H), 1.00-1.25 (m, 6H), 1.47-1.66 (m, 6H), 1.66-1.78 (m, 2H), 1.82-1.97 (m, 2H), 2.88-2.95 (m, 2H), 3.01 (dd, 1H, J1=5.6, J2=13.7), 3.21 (dd, 1H, J1=7.7, J2=13.7), 3.29 (dd, 1H, J1=8.7, J2=17.3), 3.44-3.52 (m, 1H), 3.55-3.68 (m, 2H), 3.83 (s, 3H), 4.31-4.41 (m, 1H), 4.64 (dd, 1H, J1=6.9, J2=14.1), 6.34 (dd, 1H, J1=4.1, J2=8.6), 6.568 (ddd, 1H, J1=2.5, J2=J3=8.9), 6.79 (dd, 1H, J1=2.4, J2=8.3), 7.03-7.08 (m, 1H), 7.15 (d, 1H, J=7.7), 7.22 (d, 1H, J=8.8), 7.29-7.35 (m, 3H); HPLC-MS calcd. for C30H40FN3O4 (M+H+) 526.3, found 526.5.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].CCCCCCCC(OC(CCCCCCC)=O)=O.C(OC=C)(=O)CCCCCCCCCCC.C(OC(C)C)(C)C>>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: OC(CBr)c1cccc(Cl)c1
Agent: C=COC(=O)CCCCCCCCCCC
Agent: CCCCCCCC(=O)OC(=O)CCCCCCC
Solvent: CC(C)OC(C)C
Product: O[C@@H](CBr)c1cccc(Cl)c1

Procedure:
To a mixture of 100 mg (0.4 mmol) of 2-bromo-1-(3-chlorophenyl)ethanol, 10 mg of TOYOCHIMU LIP (available from Toyobo Co., Ltd.) and 100 mg (0.31 mmol) of n-caprylic anhydride or 61 mg (0.27 mmol) of vinyl laurate as an acylating agent was added isopropyl ether to make the total volume 1 ml. The reaction mixtures were respectively allowed to undergo reaction at a temperature of 27° C. for 30 hours. After the termination of the reaction, the reaction system was subjected to centrifugal filtration to remove the supernatant. To the reaction system was then added another batch of 2-bromo-1-(3-chlorophenyl)ethanol, the acylating agent and diisopropyl ether to make the total volume 1 ml. The same reaction was then repeated twice. The initial rate and total activity at the various steps are set forth in Table 5. The initial rate is represented relative to that at the 1st step as 100%. Activity=total amount of converted BH/enzyme weight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 37.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.196 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.10 g, 36%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[CH:28][CH:27]=4)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.45) (0.158 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.032 g, 17%). MS (ISP) 374.0 [(M+H)+]; mp 199° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([F:20])=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].P(Cl)(Cl)(Cl)=O.C([O:28][P:29](OCC)([O:31]CC)=[O:30])C.COP(OC)(OC)=O>O>[CH:18]1[N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][O:9][P:29]([OH:31])([OH:30])=[O:28])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11]2[C:16](=[C:15]([NH2:19])[N:14]=[C:13]([F:20])[N:12]=2)[N:17]=1
Reactant: CCOP(=O)(OCC)OCC
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@@H]1O

Procedure:
Phosphorylation: The product from step (e) is mixed with phosphorous oxychloride in an alkyl phosphate such as triethylphosphate, or trimethylphosphate, followed by hydrolysis in water to yield the prodrug 9-β-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate or fludarabine phosphate.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[Br:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>C(Cl)Cl>[Br:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[CH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Br
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccccc1Br
Reaction time: 8 h
Yield: 96 %

Procedure:
Carboethoxymethylidene triphenylphosphorane (94 g, 270 mM) was dissolved in 350 ml of methylenechloride under nitrogen. o-Bromobenzaldehyde (31.5 ml; 270 mM) was added via an addition funnel in 125 ml of methylene chloride. The solution was allowed to stand at room temperature overnight and then the solvent was removed in vacuo. The slushy residue was taken up in 10% ethyl acetate in hexane and filtered through a one-inch pad of silica gel in a 350 ml fritted funnel with one liter of 10% ethyl acetate in hexane. Solvent removal on the rotary evaporator followed by pumping overnight gave 66.3 g of an oil, ethyl o-bromocinnamate in 96% yield. The NMR indicates a 4.5 to 1 mixture of trans to cis isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.[OH-].[Na+:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([O-:27])=[O:26])=[CH:5]2.[Na+:29]
Reactant: CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)[O-])C(C(F)(F)F)O3)cc1

Procedure:
A solution of 47.6 mg (0.119 mmole) of 6-chloro-7-(4-ethylphenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 1.5 mL of ethanol was treated with 1.18 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 51 mg (quant.) of an off-white solid: 1H NMR (CD3OD/400 MHz) 1.25 (t, 3H, J=7.7 Hz), 2. 68 (q, 2H, J=7.7 Hz), 5.79 (q, 1H, J=7.2 Hz), 6.92 (d, 2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.37 (m, 2H); MS (ES+) 399 (M+1, 100).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[OH:33])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:52]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:53][C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:72]([NH:74][C@H:75]([C:80]([NH:82]N)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:60])[CH3:58])=[O:55]>>[NH:52]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:53][C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:30][CH2:31][C:32](=[O:33])[OH:34])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:60])[CH3:58])=[O:55]
Reactant: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Yield: 76.8 %

Procedure:
By using 2.56 g of Boc-Ser(Bzl)-Thr(Bzl)-Glu-OBzl and 2.00 g of Boc-Gly-Ala-Ser(Bzl)-Leu-NHNH2, and the same procedure as in Reference Example 7 was repeated to obtain 3.13 g (yield: 76.8%) of the above-mentioned objective product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[H-].[Na+].I[CH3:16]>O1CCCC1>[CH3:16][O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: CI
Reactant: OCc1cc(Br)c2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.372 gm (0.40 mMol) 5-hydroxymethyl-7-bromobenzofuran in tetrahydrofuran was added to a mixture of 1.80 mMol sodium hydride (60% suspension in mineral oil) in 2 mL tetrahydrofuran. After stirring at room temperature for 1 hour, 204 μL iodomethane were added and stirring was continued for 2.5 hours. The reaction mixture was quenched by the addition of water and the resulting mixture was extracted well with ethyl acetate. The organic phase was concentrated under reduced pressure to provide a nearly quantitative yield of the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=O)=[O:5])#[N:2].[OH-].[Na+].Cl>N1C=CC=CC=1.O>[C:1]([C:3]1[C:4](=[O:5])[NH:6][C:7]2[C:8]([N+:15]=1[O-:17])=[CH:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)#[N:2]
Reactant: N#CCC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(=O)[nH]c2cc(Cl)c(Cl)cc2[n+]1[O-]
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of 142 (0.552 g, 2 mmol) in pyridine (4 mL), 1N NaOH (4 mL, 4 mmol) was added. The resulting mixture was stirred for 4 h, then diluted with water (50 mL) and acidified with 2N HCl to pH 2. The precipitated crude product was washed with water, dried on a filter and washed with ether (5×5 mL) to give 0.365 g (72%) of the title compound as an orange solid: mp 294°-296° C. (from EtOH); IR (KBr) 3104, 3048, 2231, 1675, 1623, 1453, 1399 and 1176 cm-1 ; 1H NMR (DMSO-d6) δ7.54 (s, 1H), 8.25 (s, 1H), 12.20 (s, 1H, N--H). HPLC: 95%; HRMS Calcd for C9H3N3O2Cl2 : 254.9602. Found: 254.9604.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[C:32]3[CH:41]=[C:40]([C:42]([O:46][CH3:47])([O:44][CH3:45])[CH3:43])[O:39][C:33]=3[C:34]([O:37][CH3:38])=[N:35][CH:36]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[C:32]2[CH:41]=[C:40]([C:42]([O:44][CH3:45])([O:46][CH3:47])[CH3:43])[O:39][C:33]=2[C:34]([O:37][CH3:38])=[N:35][CH:36]=1)=[O:28]
Reactant: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)(OC)OC)oc12
Reactant: Cc1cnccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)Nc2ccncc2C)c2cc(C(C)(OC)OC)oc12
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
A solution of 4-amino-3-methylpyridine (0.11 g) in dry N,N-dimethylformamide (20 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 1.0 ml) was added and stirring continued at 0° C. for 10 minutes. 2-(1,1-Dimethoxyethyl)-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) was added and stirring continued at room temperature for 90 minutes. The solvent was then removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml), then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl acetate gave the title compound (0.15 g) as a white solid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:25]([Cl:24])[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(C#N)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (7.50 g), 3-chloro-4-methylbenzonitrile (3.33 g), anhydrous aluminum chloride (3.00 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, it is washed with saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 3.70 g of desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][CH:8]=2)[CH2:3]1.[NH2:31][C:32]1[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([C:35]3[N:34]=[N:33][C:32]([NH2:31])=[CH:37][CH:36]=3)=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C(c2ccc3ccccc3c2)C1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cc(-c3ccc(N)nn3)ccc2C(c2ccc3ccccc3c2)C1
Temperature: 80 °C

Procedure:
To a mixture of Compound 18 (6.0 g, 15.0 mmol), 3-amino-6-chloropyridazine (3.0 g, 22.5 mmol) and cesium carbonate (14.7 g, 45.0 mmol) were added DMF (140 mL) and water (35 mL). The reaction solution was flushed with argon for 10 min, and then dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.2 g, 1.5 mmol) was added. The resultant mixture was flushed with argon for 5 min and heated at 80° C. for 1 h. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with 1:1 brine and water (2×), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (92:2:5.4:0.6 to 47:47:5.4:0.6 dichloromethane/ethyl acetate/methanol/concentrated ammonium hydroxide) to give rac-1 (3.2 g, 58%) as a light tan solid: 1H NMR (500 MHz, CDCl3) δ 7.82-7.76 (m, 4H), 7.71 (s, 1H), 7.61-7.57 (m, 2H), 7.47-7.43 (m, 2H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.80 (d, J=9.5 Hz, 1H), 4.71 (br s, 2H), 4.50 (t, J=7.0 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.74 (d, J=14.5 Hz, 1H), 3.14 (dd, J=11.5, 6.0 Hz, 1H), 2.70 (dd, J=11.5, 9.0 Hz, 1H), 2.48 (s, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[N:17]=1)=O)(C)(C)C.Cl>CO>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[NH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1
Agent: Cl
Solvent: CO
Product: Brc1ccc(-c2c[nH]c([C@@H]3CCCN3)n2)cc1
Reaction time: 2 h
Yield: 113 %

Procedure:
To a solution of (S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 7.6 mmol) in methanol (3 mL) was added 4N HCl in methanol (60 mL) at 0° C. The reaction mixture was stirred for 2 h and then concentrated to give crude hydrochloride salt of the title compound (2.51 g 100% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH2:18].[OH-].[Na+]>ClCCl>[NH2:18][CH:7]1[CH:6]([CH2:5][C:4]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:14]=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
1-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (10 g, 26.8 mmol, cf. example 3.2 were dissolved in dichloromethane (240 mL). The suspension was cooled to −10° C. and a 1 M solution of bortribromide in dichloromethane (80 mL, 80 mmol). The solution was allowed to warm to room temperature and stirring was continued for 3 h. The reaction mixture was poured on ice (1 L). The aqueous layer was made alkaline (pH 10) with 2N sodium hydroxide solution. The layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated NaHCO3 solution and water. The organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was used without further purification for the next step. Yield: 10.8 g
Reaction SMILES: C([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C@@:6]2([C@H:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:24])[CH2:21][CH3:22])[CH2:10][C:9](=[O:32])[NH:8][C@@H:7]2[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=O)C.[OH-].[Na+].O>CO>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:4][C:5](=[O:48])[C@:6]3([C@H:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=4[O:19][C:20]([CH2:30][CH3:31])([C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:24])[CH2:21][CH3:22])[CH2:10][C:9](=[O:32])[NH:8][C@@H:7]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1[C@@H]1CC(=O)N[C@H](c2cc(Cl)ccc2C)[C@@]12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1[C@@H]1CC(=O)N[C@H](c2cc(Cl)ccc2C)[C@@]12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 8 h
Yield: 53.4 %

Procedure:
At room temperature, a mixture of chiral (2′R,3R,4′S)-1-acetyl-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methanesulfonylaminocarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.027 mmol) (RO5319796-000), NaOH (2 mg, 0.05 mmol), H2O (0.5 mL) and methanol (2 mL) was stirred overnight. Then methanol was removed by vacuum. The aqueous solution was acidified by addition of concentrated HCl to “pH” 1-2 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid (10 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:28]1(S(N)(=O)=O)C=CC=C[CH:29]=1>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12][S:13]([C:16]2[CH:20]=[CH:19][CH:18]=[CH:29][CH:28]=2)(=[O:14])=[O:15])[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1ccccc1
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2ccccc2)c2ccccc2C1=O

Procedure:
5.2.18 Ethyl 2-(1-oxo-4-(phenylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (8c) was prepared according to the procedure for 8a except using benzenesulfonamide, which afforded 131.8 mg (31.7%) title compound as a yellow solid, m.p.: 93-95° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[CH3:10]
Reactant: CCNCC
Reactant: Fc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(I)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2 g, 8.97 mmol), diethyl amine (2.77 ml, 26.9 mmol, 3 eq) and K2CO3 (2.48 g, 17.94 mmol, 2 eq) in DMF (20 mL) is stirred for 18 h at 100° C., allowed to cool to rt, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (Hex/Et2O, 98:2) to afford 2.3 g of the title compound as a yellow oil: ESI-MS: 277.1 [M+H]+; TLC: Rf=0.52 (Hex/Et2O, 98:2).