Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[S:39][C:40]([C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[CH:41][N:42]=1>>[C:3]([C:2]([CH3:36])([CH3:1])[CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[S:39][C:40]([C:43]([NH:45][CH:46]4[CH2:47][CH2:48]4)=[O:44])=[CH:41][N:42]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC3CC3)s2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.262 min, m/z=529.3; 1H NMR (CDCl3) 0.63 (m, 2H), 0.86 (m, 2H), 1.30 (s, 3H), 1.43 (s, 3H), 1.52 (d, 3H), 2.02 (s, 2H), 2.29 (m, 1H), 2.81-2.99 (m, 2H), 5.62 (m, 1H), 6.50 (s, 1H), 6.89 (d, 2H), 7.37 (m, 5H), 7.60 (m, 2H), 8.14 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:13][O:14][C:15](Cl)=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:14][CH3:13])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)OCC(F)(F)F
Temperature: 25 °C

Procedure:
2,2,2-trifluoroethanol (105 g 1.05 mol), pyridine (87 g 1.1 mol) and 300 mL of methylene chloride were combined in a 1 L 3-neck round bottom flask. The flask was equipped with an overhead stirring mechanism, thermocouple, addition funnel, cold water condenser, and a dry nitrogen bubbler. The reaction flask was kept cool using a dry ice/acetone bath to keep the temperature in the range of −20° C. to −15° C. Methylchloroformate (100 g 1.05 mol) was added via an addition funnel at such a rate that the temperature was kept in the range of −20° C. to −15° C. Once the addition of the methylchloroformate was complete the reaction mix was allowed to warm to room temperature. The reaction mix was then quenched with 100 mL water. The methylene chloride solution was separated from the water and washed with 2×100 mL of 1N HCl. The methylene chloride was removed by distillation and the product was purified using fractional distillation on a concentric tube column (b.p.=90.0° C., purity=99.7%). The structure mass was confirmed by GC/MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: NS(=O)(=O)c1ccccc1Br
Product: NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 2-bromobenzenesulfonamide. MS (ESI): mass calcd. for C19H16FN3O3S, 385.09; m/z found, 386.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.14-8.11 (m, 1H), 7.80 (d, J=1.0, 1H), 7.73-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.61-7.52 (m, 2H), 7.39-7.31 (m, 3H), 4.40-4.34 (m, 2H), 3.75-3.69 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[O:16][C:15]2=[O:29])[CH:12]=1.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][C:3]([CH2:2][Cl:1])=[O:4])=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)[O:16][C:15]2=[O:29])[CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Neat chloroacetyl chloride (0.45 g, 5.6 mmol) was added dropwise to a stirred cold (0° C.) solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.8 g, 4.9 mmol) and anhydrous pyridine (0.45 g, 5.5 mmol) in anhydrous dichloromethane (30 mL). The resulting mixture was allowed to warm to room temperature and stirred for 4 hr. The dichloromethane was rotary evaporated and the residue was partitioned between diethylether-ethyl acetate and dilute HCl. The organic layer was washed with saturated sodium bicarbonate, water and brine and then dried (MgSO4). Evaporation of the solvents followed by recrystallization of the residue from acetone/hexanes afforded the title compound as off-white crystals (2.2 g, 98%). MS m/e 447 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:26]1[CH2:30][CH2:29][N:28]([N:31]=[CH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]1=[O:39])([C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[CH3:40][O:41][C:42]1[CH:60]=[CH:59][C:45]([CH2:46][O:47][C:48](SC2N=C(C)C=C(C)N=2)=[O:49])=[CH:44][CH:43]=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:32](=[N:31][N:28]1[CH2:29][CH2:30][N:26]([C@@:5]2([C:10]([O:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[NH:1][C:48]([O:47][CH2:46][C:45]3[CH:59]=[CH:60][C:42]([O:41][CH3:40])=[CH:43][CH:44]=3)=[O:49])[CH2:6]2)[C:27]1=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OC(c3ccccc3)c3ccccc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H]2C(=O)N3C[C@@](C(=O)OC(c4ccccc4)c4ccccc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
In 80 ml of methylene chloride was dissolved 7.50 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 5 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine. The mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with 80 ml of water, and the resulting mixture was adjusted to pH 7.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/acetone=1/0 to 25/1) to obtain 8.36 g (yield: 85.2%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(p-methoxybenzyloxycarbonylamino)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][CH2:4][CH2:5][N:6]([CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.C(N(CC)CC)C>[CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][CH2:4][CH2:5][N:6]([CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][C:10]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:9][CH:8]=1
Reactant: CCN(CCO[Si](C)(C)C)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCO[Si](C)(C)C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture containing 10.9 g, that is 30 mmole, 4-[(2-trimethylsiloxyethyl)ethylamino]iodobenzene from the previous step, 1.0 g, that is 1.4 mmole bis(triphenylphosphine)palladium(II) chloride from Aldrich Chemical Co., and 74 mg, that is 0.75 mmole cuprous chloride, from Aldrich Chemical Co. in 50 m triethylamine was stirred and degassed under nitrogen for 15 minutes. Next 3.5 g, that is, 36 mmole trimethylsilylacetylene from Aldrich chemical Co. was added with vigorous mechanical stirring at room temperature and the final mixture was stirred at 80° C. for 1 hour. The cooled reaction mixture was filtered, diluted with ethyl ether and extracted with dilute HCL. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The dark residue was flash column chromatographed on silica gel with 4% ethyl acetate-hexane to give 9.2 g of yellow oil at a 92% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11](/[CH:12]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A mixture of 3-benzyloxy-benzaldehyde (5.16 g, 24.3 mmol) described in Manufacturing Example 61-1-1, nitromethane (2.16 mL, 48.6 mmol), ammonium acetate (2.81 g, 36.5 mmol) and acetic acid (50 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (5.50 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 20 step B, 150 mg, 0.44 mmol) and 3-chloro-4-fluorophenylboronic acid (62 mg, 0.35 mmol) as off white solid (70 mg, 41%). LC-MS: 392 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1[C:11]([CH2:24][O:25][CH3:26])=[C:12]([C:21](O)=[O:22])[N:13]=[CH:14][C:15]=1[NH:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1NC=CN=1)(C1[NH:30]C=CN=1)=O>O1CCCC1>[O:1]([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1[C:11]([CH2:24][O:25][CH3:26])=[C:12]([C:21]([NH2:30])=[O:22])[N:13]=[CH:14][C:15]=1[NH:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(c1ncc[nH]1)c1ncc[nH]1
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Solvent: C1CCOC1
Product: COCc1c(C(N)=O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reaction time: 5 h
Yield: 74.3 %

Procedure:
2.7 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid is added to a solution of 30 mmol of thionyldiimidazole in 150 ml of tetrahydrofuran. The reaction mixture is stirred for 5 hours and filtered. The filtrate is mixed with 12 ml of 25% NH3 in water, stirred overnight and concentrated in a vacuum to 50 ml. After addition of 100 ml of water, 2 g of the desired product is obtained as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:13]([F:27])=[CH:12][N:11]=1>>[CH3:26][O:25][C:18]1[C:17]([NH:16][C:14]2[C:13]([F:27])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[CH:22][CH:21]=[C:20]([O:23][CH3:24])[N:19]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.98 (bs, 2H), 8.20 (d, 1H, J=5.4 Hz), 7.72 9m, 1H), 6.90 (t, 1H, J=7.8 Hz), 6.81 (m, 2H), 6.42 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H); LCMS: purity: 94%; MS (m/e): 358 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1nccc(C(=O)O)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nccc(C(=O)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (20 g, 117.7 mmol) in CH2Cl2 (100 mL) is added oxalyl chloride (17.2 g, 197 mmol) and DMF (20 drops). The reaction solution is stirred at room temperature for 18 hours after which the solvent is removed in vacuo to afford 21.2 g, (95% yield) of the desired product as a dark green solid.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH3:22])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: ClCCl
Solvent: CO
Product: COC(C)(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 179.2 %

Procedure:
A solution of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 120 mg, 0.346 mmol) and TFA (0.013 mL, 0.173 mmol) in methanol (2 mL) was stirred at rt over a weekend. The mixture was diluted with DCM, washed with 1 M aqueous sodium hydroxide and water, dried and concentrated. The residue was combined with that from another reaction done with 20 mg of Intermediate 73-2, and purified by column chromatography (eluting with hexane-EtOAc) to provide 4-bromo-7-(2-methoxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (112 mg, 77%). 1H NMR (400 MHz, chloroform-d) δ 10.53 (1 H, br. s.), 8.68 (1 H, d, J=8.36 Hz), 7.59 (1 H, d, J=1.10 Hz), 7.36-7.44 (3H, m), 3.13 (3 H, s), 1.64 (6 H, s). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [Na].C([NH:5][C:6]1[C:14]2[CH:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:12]3[O:11][C:10]=2[C:9]([C:19]([O:21]C)=[O:20])=[CH:8][C:7]=1[Cl:23])(=O)C>CO.[OH-].[Na+]>[NH2:5][C:6]1[C:14]2[CH:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:12]3[O:11][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][C:7]=1[Cl:23]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Reaction time: 48 h

Procedure:
To a solution of 0.3 g of sodium in 15 ml methanol is added 0.6 g of methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate. Stirring is continued at 60° C. for two days. This is then diluted with 5 ml 1N sodium hydroxide and stirring continued at 60° C. overnight. The methanol is removed in vacuum, diluted with water, filtered, acidified with acetic acid, filtered, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. This is purified by crystallization from ethyl acetate/ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NCc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixture of (RS)-2-(4-amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 4-chlorobenzaldehyde (33.3 mg) and AcOH (123 μl) in THF (2 ml) was added sodium triacetoxyborohydride (68.5 mg). The reaction mixture was then capped and the mixture was shaken at 60° C. for 3 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 65% EtOAc in hexanes) to afford (RS)-2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg, 78%) as a colourless oil. MS (ISP): 405.4 ([{37Cl}M+H]+), 403.4 ([{35Cl}M+H]+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (3.6 g, 7.2 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (3.8 g, 95%).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:8](OC(=O)C)(=[O:10])[CH3:9].[S:15]([N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClCCl>[C:8]([C:27]1[CH:28]=[CH:29][N:25]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH:26]=1)(=[O:10])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
In a 1-liter three-neck flask fitted with a thermometer, a 50 cm3 funnel and a condenser with calcium chloride guard, 500 cm3 of dichloromethane and 80 g anhydrous aluminum chloride (600 mmoles) were added. 30 cm3 of acetic anhydride (320 mmoles) was dropwise added. The solution was stirred during 10 minutes. Then a 60 cm3 of dichloromethane solution containing 27 g of 1-tosyl pyrrole 1 (122 mmoles) was dropwise added. The stirring was maintained during 2 hours at room temperature, then the resulting solution was poured on 500 cm3 of water-ice mixture. After decantation, the aqueous layer was extracted with dichloromethane. The combine organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of purple crystals 2 (M=263, yield: 96.7%). F (° C)=87 (purified by chromatography). NMR: (CDCl3) ppm 7.7 d J(Hz) 8 2H; 7.2 4H; 6.62 2H; 2.35 s 6H.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][C:38]([F:40])=[CH:37][C:36]=3[F:41])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Fc1cc(F)c(CBr)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2c(F)cc(F)cc2F)c1=O
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s, 1 H), 10.08 (br. s, 1 H), 7.11-7.19 (m, 2 H), 5.06 (s, 2 H), 4.61 (t, J=12.00 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.59 (t, J=13.01 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.06-1.17 (m, 1 H).