Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:39](Cl)(=[O:41])[CH3:40]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][N:30]([C:39](=[O:41])[CH3:40])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CNCc4ccccc4)cc3)cc2)CC1
Reactant: CC(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CN(Cc4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(3-benzylamino-2-hydroxy-propyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][C:30]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:39]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][C:30]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:39]=2)[C:25]([F:28])([F:26])[F:27])[N:3]=1
Reactant: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCC)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][N:36]([CH2:2][C:3]3[N:13]([CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: N#Cc1ncc2cc(CBr)n(CCC3CCCCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4cnc(C#N)nc4n3CCC3CCCCC3)CC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (290 mg, 0.84 mmol) in DMF (1.7 ml), 2,8-Diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (201 mg, 0.84 mmol) and potassium carbonate (138 mg, 1.0 mmol) are added. The mixture is stirred at room temperature under nitrogen atomosphere for 14 h. The reaction mixture is diluted with water and extracted with AcOEt (twice). The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 8-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in 71% yield. Rf=0.45(n-hexane:AcOEt=1:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:16](O)(=[S:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C(CC(C)(C)C)(C)C.C(OCC)(=O)C.O>[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[S:18])[CH3:17]
Reactant: CC(O)=S
Reactant: COC(=O)CCCCCCCCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)CC(C)(C)C
Product: COC(=O)CCCCCCCCCCC(C)=S
Yield: 94.3 %

Procedure:
Compound 103 (17.8 g, 64 mmol), thioacetic acid (9.7 g, 9.0 ml, 128 mmol), methyltrioctylammonium chloride (0.5 g), cesium carbonate (25 g, 77 mmol), dichloromethane (95 ml) and water (95 ml) were stirred at room temperature for 15 h. The reaction was monitored by TLC (SiO2, ethyl acetate:isooctane, 1:5). The mixture was extracted with dichloromethane and the combined extracts were dried (Na2SO4) and concentrated. Distillation gave pure 104 (15.6 g, 89%) with b.p. 137°-139° (0.1 torr) and m.p. <25° (from isooctane). 1H-NMR (CDCl3, Me4Si) δ 3.67 (s, 3H, MeO), 2.86 (t, 2H, J=7.1 Hz, S--CH2), 2.32 (s, 3H, MeCO), 2.30 (t, 2H, J=7.7 Hz, CH2CO). 13C-NMR (CDCl3, Me4Si) δ 195.9, 174.1 (CO), 51.3, 34.0, 30.5, 29.4, 29.3, 29.2, 29.1, 29.0, 28.9, 28.7, 24.8.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCCC3)c1
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCCC3)cc1
Yield: 73.9 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (0.100 g, 0.36 mmol) was reacted with 4-aminophenethyl alcohol (0.059 g, 0.43 mmol) to afford the title compound (0.101 g, 100%) as a yellow solid. MW=379.88. 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (s, 1H), 8.25-8.16 (m, 2H), 7.69-7.64 (m, 2H), 7.52-7.47 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.2 Hz, 1H), 3.66-3.58 (m, 2H), 2.78-2.68 (m, 4H), 2.63-2.57 (m, 2H), 1.89-1.77 (m, 4H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc2ccccc2s1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(C=Cc2nc3ccccc3s2)c1
Yield: 70 %

Procedure:
A solution of 12.4 g (67 mmol) of 2-chloro-5-nitrobenzaldehyde and 10.0 g (67 mmol) of freshly distilled 2-methylbenzothiazole in 60 ml of acetic anhydride was refluxed for 5 h. The precipitated yellow solid was collected by filtration and recrystallized from toluene to afford 14.9 g (70%) of 2-(2'-chloro-5'-nitrostyryl)benzothiazole (IIIa); mp 188°-189° C., UV λmaxEtOH nm (ε) 214(16808), 332.5(28445); 1H-NMR δTMSCDCl3 (ppm) 8.58 (d, J=2.7 Hz, 1H), 8.16-7.26 (complex pattern, 8H); 13C--NMRTMS δTMSDMSO-d6 (ppm) 165.0, 154.0, 147.1, 140.2, 135.3, 134.9, 131.1, 130.7, 127.3, 126.7, 126.0, 124.0, 123.6, 121.6, 121.0; IR νmaxKbr (cm-1) 1521.8, 1455.4, 1342.4, 1116.3, 1046.3, 951.3, 873.34, 826.1, 724.1, 737.4, 728.3. Anal. Calcd. for C15H9CiN2O2 : C, 56.87, H, 2.86, N, 8.84; Found: C, 56.84; H, 2.86, N, 8.73.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][C:26]([CH3:45])([CH3:44])[N:27]([CH2:31][C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[CH2:28]2)=[CH:23][C:22]=1[O:46][Si](C(C)C)(C(C)C)C(C)C.COC1C=C(C=CC=1)CN1C(C)(C)CC2C(=CC(OC)=C(O)C=2)C1>>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][C:26]([CH3:44])([CH3:45])[N:27]([CH2:31][C:32]3[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=3)[CH2:28]2)=[CH:23][C:22]=1[OH:46]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)N(Cc1cc(OC)c(OC)c(OC)c1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(CN2Cc3cc(OC)c(O)cc3CC2(C)C)c1
Agent: [F-]
Product: COc1cc2c(cc1O)CC(C)(C)N(Cc1cc(OC)c(OC)c(OC)c1)C2
Yield: 71 %

Procedure:
TBAF deprotection of 227 (in analogy to the synthesis of 228) afforded the title compound (95 mg, 71%) as a yellow oil that crystallised on trituration with DCM/hexane to afford a yellow powder. mp=143-147° C. 1H NMR (270 MHz; CDCl3) 1.17 (6H, s, 2×CH3), 2.66 (2H, s, CH2), 3.52 (2H, s, CH2), 3.60 (2H, s, CH2), 3.82 (3H, s, OCH3), 3.83 (6H, s, 2×OCH3), 3.84 (3H, s, OCH3), 5.44 (1H, brs, OH), 6.50 (1H, s, CH), 6.53 (1H, s, CH), 6.60 (2H, s, 2×CH). 13C NMR (100 MHz; CDCl3) 23.82 (CH3), 42.41 (CH2), 50.02 (CH2), 52.53 (C), 53.78 (CH2), 55.88 (OCH3), 56.05 (OCH3), 60.84 (OCH3), 105.02 (CH), 110.68 (CH), 111.73 (CH), 125.62 (C), 126.85 (C), 136.44 (C), 143.54 (C), 145.02 (C), 153.08 (C). LC/MS (ES−) tr=1.17 min, m/z 386.26 (M−H)−. HRMS (ES+) calcd. for C22H30NO5 (M++H) 388.2118, found 388.2111. HPLC tr=2.73 min (>82%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[C:13]=1[F:22]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl alcohol (29.4 mL) in DMF (300 mL) was added sodium hydride (60% oil, 11.3 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1,2,3-trifluoro-4-nitrobenzene (20.0 g), and the mixture was stirred with heating at 80° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([NH2:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2.[N:15]([O-:17])=[O:16].[Na+].II>C(OCC)(=O)C.C(O)CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([NH2:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7]2
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: II
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Yield: 24 %

Procedure:
To a solution of 8-fluoro-2H-1-benzopyran-5-carboxamide (4.46 g, 23.1 mmol) in ethyl acetate (220 mL), ethylene glycol (4.0 mL) and a solution of sodium nitrite (6.52 g, 92.4 mmol) in H2O (11 mL) were added followed by iodine (9.0 g, 34.7 mmol). The reaction mixture was refluxed for 24 hours and during this time H2O (22 mL) and ethylene glycol (4.0 mL) were added portionwise. The reaction mixture was cooled, diluted with ethyl acetate, washed with a 5% solution of NaS2O3, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give a crude yellow solid. The solid was recrystallized from absolute ethanol to give 1.3 g (24% yield) of sparkly yellow crystals as the title compound (mp 227.8-228.2° C.). EIMS (70 eV) m/z (relative intensity) 238 (57, M+), 221 (100), 192 (71), 191 (46), 190 (10), 148 (14), 109 (16), 94 (12).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:25]=[C:24]([F:26])[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=4[F:31])[C:15]3=[O:32])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:31][C:21]1[CH:22]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([F:26])=[CH:25][C:20]=1[O:19][C@H:16]1[CH2:17][CH2:18][N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15]1=[O:32]
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)cc1F
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: C1COCCO1
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(-c5ccccc5)cn4)CC3)C2=O)cc1F
Temperature: 95 °C
Yield: 64 %

Procedure:
(S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (Example 90; 80 mg, 0.15 mmol) was dissolved in dioxane (2 mL) and phenylboronic acid (28 mg, 0.23 mmol), 2M Na2CO3 (301 μL, 0.60 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added and the reaction heated to 95° C. under nitrogen for 2 hours. The reaction was cooled to ambient temperature and partitioned between water and CH2Cl2, and the organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (70% EtOAc in hexanes) to afford impure material. The material was then purified on C18 reverse phase chromatography (20 to 95% ACN in water) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-phenylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (51 mg, 0.096 mmol, 64% yield) as a white solid. Mass spectrum (apci) m/z=529.3 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17]([OH:19])=O.CN(C)C=O.[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[NH:37][CH3:38])[CH3:26]>ClCCl.N1C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[N:37]([C:17](=[O:19])[CH2:16][C:9]1[C:10]([F:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[Cl:7])[CH3:38])[CH3:26]
Reactant: O=C(O)Cc1c(F)ccc(F)c1Cl
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1NC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)cc(C)nc1N(C)C(=O)Cc1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
Oxalyl chloride (0.19 ml) was added dropwise to a solution of (2-chloro-3,6-difluoro-phenyl)-acetic acid (373 mg) in dichloromethane (5 ml) at ambient temperature. A drop of N,N-dimethylformamide (“DMF”) was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated to give a colourless oil which was dissolved in dichloromethane (5 ml). The mixture was added dropwise to a slurry of 4-chloro-6-methyl-2-methylamino-nicotinic acid ethyl ester (Example 4.1) (413 mg) and pyridine (0.16 ml) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:4) to give 4-chloro-2-{[2-(2-chloro-3,6-difluoro-phenyl)-acetyl]-methyl-amino}-6-methyl-nicotinic acid ethyl ester as a yellow solid (299 mg). 1H NMR (400 MHz, CDCl3): 7.32 (bs, 1H), 7.00-7.05 (m, 1H), 6.90-6.96 (m, 1H), 4.43-4.45 (m, 2H), 3.66 (s, 2H), 3.24 (m, 3H), 2.60 (s, 3H), 1.37-1.40 (t, 3H) ppm.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[SH:5])(C)C.[H-].[Na+].I[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[C:17]([Cl:31])[C:16]=1[Cl:32].CN(C=O)C>C1COCC1.C1(C)C=CC=CC=1.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.CCOC(C)=O>[Cl:31][C:17]1[C:16]([Cl:32])=[C:15]([SH:5])[CH:20]=[CH:19][C:18]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)c(Cl)c1Cl)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S)c(Cl)c1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Triisopropylsilane thiol (2.0 ml) was added to a stirred suspension of sodium hydride (0.37 g, 60% mineral oil dispersion) in anhydrous THF (30 ml) cooled to 0° C. under argon. After 20 minutes at this temperature the reaction mixture was added to a stirred suspension of (R)-N-[4-iodo-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 4) (4.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.86 g) in anhydrous toluene (40 ml). The mixture was heated to 85° C. for 5 hours and DMF (10 ml) was added to obtain a clear solution. Heating was continued for a further 17 hours. The mixture was allowed to cool to ambient temperature, EtOAc (200 ml) was added and the mixture washed with brine (3×100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 1-50% EtOAc/isohexane to give the title compound (0.448 g) as an orange solid. NMR: 1.58 (s, 3H), 7.55 (d, 1H), 7.66 (d, 1H), 7.73 (s, 1H), 9.80 (s, 1H); m/z: 332.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].C[O-].[Na+].[C:15](O)(=[O:17])C>CO>[CH3:15][O:17][CH2:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)O
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(CC(=O)OC)C(=O)OC
Reaction time: 96 h
Yield: 80.3 %

Procedure:
200 g of dimethyl itaconate are dissolved, together with 5.9 g of sodium methoxide, in 650 ml of methanol and the solution is left to stand for four days. The solution is then acidified with acetic acid and fractionally distilled. 240 g (83.4% of the theoretical yield) of dimethyl 2-methoxymethylsuccinate are obtained, at a boiling range of from 109° to 112° C. After the ester has been hydrolyzed with 2N HCl, the free acid is obtained in a yield of 80.3% of the theoretical yield.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C1C2C(=CC=CC=2)CCN1.C(O)C>[CH2:22]1[C:20]2[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=2)[CH2:6][CH2:26][N:23]1[CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 21. Purity by LC/MS=98%, [M+H]+=419.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>C(#N)C.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:15](=[O:17])[CH3:16])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1Cl
Reaction time: 0.67 h

Procedure:
To a solution of the product obtained in step 2 (0.40 mg, 1.71 mmol) in ACN (3 ml) was added acetic anhydride. Concentrated sulphuric acid (2.8 μl, 5 mg, 51 μM) was added at 60° C. and the reaction mixture was stirred for 40 min at that temperature. The cooled reaction mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The desired product was obtained (yield: 460 mg, 97%) and used in the following step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1cc2ccccc2[nH]1
Yield: 62.6 %

Procedure:
Indole 2-carboxaldehyde (6.72 g, 46.3 mmol) was dissolved in dry toluene (450 ml) and treated with (formylmethylene)triphenylphosphorane (21.3 g, 70 mmol). The reaction mixture was treated under reflux for 4 h, allowed to cool and chromatographed over silica gel using toluene (2×500 ml) and then hexane/EtOAc (3:1) (2×500 ml) as the eluent. Evaporation of the solvent and recrystallization of the residue from toluene yielded 4.96 g (62.6%) of the title compound, m.p.=203-204° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ncc(F)cc4F)c3)cnc2n1

Procedure:
4-Fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid was coupled with 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol and crystallisation from toluene/isohexane gave 2-[3-(3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol: δH (400 MHz, DMSO) 8.96 (1H, d, J 7), 8.72 (1H, d, J 2), 8.17 (1H, dd, J 2 and 1), 7.93 (1H, s), 7.85-7.91 (2H, m), 7.59 (1H, dd, J 10 and 8), 7.40 (1H, d, J 7), 5.51 (1H, s), 1.51 (6H, s); m/z (ES+) 385 (MH+).