Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C@@:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:4]2[CH2:5][CH2:6][CH2:7][C@@:3]2([CH3:2])[C:8]([OH:10])=[O:9])=[O:18])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Br
Product: C[C@@]1(C(=O)O)CCCN1C(=O)c1ccc(C#N)cc1

Procedure:
By reacting 2-methyl-L-proline hydrobromide with p-cyanobenzoyl chloride analogously to Example 2b) there is obtained 1-(p-cyanobenzoyl)-2-methyl-L-proline. MS (EI): 213 (M-COOH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[C:27]([F:28])[CH:26]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)c(F)c1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Yield: 89.9 %

Procedure:
The title compound (D109) (87 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 3,4-Difluorophenol (36.87 mg, 0.284 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccccn1
Yield: 43 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), pyridine-2-sulfonyl chloride Intermediate 18) (163 mg, 0.92 mmol), pyridine (0.12 ml, 1.54 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (100 mg, 43%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[CH3:21][NH2:22]>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:19])[C:9]3[CH2:20][CH:6]([C:4]([NH:22][CH3:21])=[O:3])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CN
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Solvent: CCO
Product: CNC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 70 °C
Reaction time: 50 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-methyl-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (4.5 g, 0.016 mole) in 100 ml of absolute ethanol, was added methylamine (40% aqueous solution, 15 ml, 6 g, 0.18 mole). The mixture was stirred at 70° C. for 50 hours in a sealed tube. The mixture was concentrated to a brown solid (~5 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to a white solid, 3.0 g, mp 164°-165° C. A sample of this material was recrystallized from ethanol to afford the product as a white solid, mp 166°-167° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([N:43]([CH3:57])[S:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(Cl)Cl.[N+](C)([O-])=O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:36][C@H:37]1[CH2:38][CH2:39][C@H:40]([N:43]([CH3:57])[S:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:51][CH:52]=2)(=[O:45])=[O:46])[CH2:41][CH2:42]1
Reactant: CN([C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: OCCCBr
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CN([C@H]1CC[C@H](COCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
[following a procedure of Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods. 41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35(28), 5075-6.]. A solution of 0.175 ml (2 mmol) 3-bromo-1-propanol and 0.48 ml 2,6-di-tert-butylpyridine in 1 ml CH2Cl2 was treated at 0° C. with a solution of 0.35 ml (2.1 mmol) trifluoromethansulfonic anhydride in 0.5 ml CH2Cl2. After 2.5 h at 0° C., the violet solution was evaporated, dissolved in 1 ml nitromethane and treated with a solution of 0.375 g (1 mmol) trans-N-(4-Hydroxymethyl-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 0.45 ml (2 mmol) 2,6-di-tert-butylpyridine in 3 ml nitromethane (during 3 min). The reaction was heated (60° C.) for 3.5 h and then extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 9:1) yielded 0.3 g (64%) of trans-N-[4-(3-Bromo-propoxymethyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 452 (M−F, 1Br).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:30][C:31]1[C:32]([C:39]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=2[F:20])=[O:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ncc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 5-chloro-2-(methylthio)-4-pyrimidinecarboxylic acid (16.44 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.017 g, 38%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.73-8.81 (m, 2H), 7.63 (t, 1H), 7.47-7.54 (m, 1H), 7.42-7.47 (m, 1H), 7.36-7.41 (m, 2H), 4.69 (d, 2H), 2.56 (br. s., 3H). LCMS m/z 496.9 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]([C@H:17]1[N:22]2[CH2:23][CH2:24][NH:25][CH2:26][C@H:21]2[CH2:20][N:19]([CH2:27][C:28]2[CH:33]=[C:32]([N:34]3[C:38]([C:39]([F:42])([F:41])[F:40])=[N:37][N:36]=[N:35]3)[CH:31]=[CH:30][C:29]=2[O:43][CH3:44])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[C:77](OCC)(=[O:79])C>ClCCl.O.C(O)=O>[ClH:1].[ClH:1].[CH:4]([C@H:17]1[N:22]2[CH2:23][CH2:24][N:25]([CH:77]=[O:79])[CH2:26][C@H:21]2[CH2:20][N:19]([CH2:27][C:28]2[CH:33]=[C:32]([N:34]3[C:38]([C:39]([F:42])([F:41])[F:40])=[N:37][N:36]=[N:35]3)[CH:31]=[CH:30][C:29]=2[O:43][CH3:44])[CH2:18]1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CNCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: O=CO
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CN(C=O)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Formic acid (28 μl ) was added to a mixture of (4R,9aS)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (100 mg), N,N-diisopropylethylamine (129 μl), 1-hydroxybenzotriazole (30.1 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (34.2 mg) in dichloromethane (2.0 ml). After being stirred for 18 hours at room temperature, the resulting mixture was poured into water, and the whole was extracted with ethyl acetate, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound was collected and evaporated under reduced pressure and resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (6R,9aR)-6-benzhydryl-8-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine-2-carbaldehyde dihydrochloride (100.1 mg) as colourless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[Sn](Cl)Cl.O>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:19]([F:21])([F:20])[F:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1ccc(N)c(C(F)(F)F)c1
Yield: 89.2 %

Procedure:
A suspension of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460 mmol) and water (16.6 g, 920 mmol) in ethanol (500 mL) was heated at reflux for four hours. The reaction mixture was concentrated under reduced pressure; the residue was treated with ethyl acetate (300 mL) and aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (10:1) to give 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (31.1 g, 89%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=8.4, 2.1 Hz), 6.69 (d, 1 H, J=8.4 Hz), 4.10 (m, 4 H), 3.54 (t, 1 H, J=7.8 Hz), 1.91 (m, 1H), 1.58 (m, 1 H), 1.44 (m, 1 H), 1.21 (t, 3 H, J=6.9 Hz), 0.90 (d, 3 H, J=6.6 Hz), 0.89 (d, 3 H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 174.14, 143.45, 132.22, 128.58, 125.91 (q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29 Hz), 60.60, 48.54, 42.35, 25.77, 22.46, 22.18, 14.04.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Br)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:15]=1[CH:16]=[O:17].Cl>O1CCCC1.O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][C:15]=1[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:17]
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccn1)c1cc(OC(F)(F)F)ccc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromopyridine (380 mg) in anhydrous tetrahydrofuran (3 mL) is slowly added a 1M solution of isopropylmagnesium bromide in tetrahydrofuran (2.64 mL) at room temperature. After stirring for 2 hours, 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.50 mL) is added and the reaction mixture stirred for 2 hours. After hydrolysis with water and 3N hydrochloric acid, the mixture is washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with ethyl acetate twice. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-5-trifluoromethoxyphenyl)pyridin-2-ylmethanol as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1ccc2ncc(I)n2c1
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: COc1cc(-c2cnc3ccc(Br)cn23)cc(OC)c1OC
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A reaction flask was charged with 6-bromo-3-iodoimidazo[1,2-a]pyridine (2.0 g, 6.2 mmol), (3,4,5-trimethoxyphenyl)boronic acid (1.44 g, 6.8 mmol), 2M. aq. Na2CO3 (8 mL, 16 mmol), 1,4-dioxane (50 mL) and a stir bar. The contents were degassed by vacuum and back filled with argon in three times while stirring. Subsequently, catalyst Pd(PPh3)4 (0.35 g, 0.30 mmol) was added to the reaction contents, repeated degassing cycles and heated at 90° C. for 12 h. Reaction mixture was cooled and filtered the biphasic reaction mixture through Celite® and concentrated the filtrate. The crude solid residue was partitioned between CH2Cl2(150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate (2.2 g) was subjected to purification by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 30-60% EtOAC/hexanes as an eluting solvent) to obtain 6-bromo-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine as a white solid (1.0 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:8][CH2:9][CH:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)[OH:11]
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
To 5-[2-(dibenzylamino)acetyl]salicylamide (75.0 g, 0.200 mmol) and acetic acid (24.0 g, 0.40 mmol) in 1.0 liter methanol, add 5% palladium/carbon (40.0 g). Hydrogenate at 3 atmospheres for 16 hours. Filter the catalyst, concentrate slightly and adjust the volume to give a solution of the title compound of the desired molarity.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: OCCCCCCCCCCBr
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCCCCCCCBr
Reaction time: 18 h
Yield: 85 %

Procedure:
2,2-dimethyl-propionic acid 10-bromodecyl ester was prepared in 85% yield by treatment of 10-bromodecane-1-ol with trimethylacetyl chloride in the presence of pyridine and 4-dimethylaminopyridine at room temperature in dithlcromethane. After 18 hrs, the reaction was quenched by the addition of dilute hydrochloric acid worked up and filtered through silica to provide 2,2-dimethyl-propionic acid 10-bromodecyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:40][CH:41]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[C:5]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[N:40][CH:41]=4)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.723 g, 1.51 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (Example 190, Step 2, 0.317 g, 1.52 mmol) in THF (5 mL) was treated dropwise with LiHMDS (4.52 mL, 4.52 mmol) at 0° C. The dark red mixture was stirred at 0° C. for 30 min. Water (0.2 mL) was added to quench the reaction. The reaction mixture was partitioned between saturated aqueous ammonium chloride (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g, eluent: EtOAc in hexanes 0%-35%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.697 g, 69% yield) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 11.77 (s, 1H); 8.74 (d, J=2.34 Hz, 1H); 8.39 (br. s., 1H); 8.22 (s, 1H); 7.79-7.94 (m, 2H); 7.28 (br. s., 1H); 7.19 (t, J=9.28 Hz, 4H); 6.86 (dd, J=8.18, 3.95 Hz, 4H); 4.83 (d, J=11.55 Hz, 4H); 3.80 (d, J=4.97 Hz, 6H); 2.58 (s, 3H); 1.53 (s, 9H). m/z (ESI, +ve ion) 669.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14](C(O)=O)[O:15][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]>[Cu].C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=O>[CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[CH:14][O:15][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3oc(C(=O)O)cc3nc21
Agent: [Cu]
Agent: CCOC(=O)c1ccccc1C(=O)OCC
Product: CCn1cc(C(=O)O)c(=O)c2cc3occc3nc21
Yield: 51.7 %

Procedure:
A mixture of 9.5 g of 5,8-dihydro-5-ethyl-8-oxofuro-[3,2-b]-1,8-naphthyridine-2,7-dicarboxylic acid (Compound X where R1 =C2H5), 0.8 g of copper powder and 250 ml of diethyl phthalate was heated at 250° to 260° C. for 25 minutes. After cooling, the reaction mixture was separated by partitioning between chloroform and aqueous potassium carbonate solution. The aqueous layer which separated out was acidified with hydrochloric acid and extracted with chloroform. The extract was treated with charcoal, and washed with water, dried and concentrated. The crystals precipitated by adding ethanol were collected by filtration to obtain 4.2 g of 5,8-dihydro-5-ethyl-8-oxofuro[3,2-b]-1,8-naphthyridine-7-carboxylic acid (Compound Ia where R1 =C2H5).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.O.O.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>C(O)(C)C>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[C:38]([O-:43])(=[O:42])[C:39]([O-:41])=[O:40]
Reactant: O=C(O)C(=O)O
Agent: O=C1[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2C(=O)N1C[C@@H]1CCCC[C@H]1CN1CCN(c2nsc3ccccc23)CC1
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A mixture consisting of isopropanol (600 mL), lurasidone base (57 g) and oxalic acid dihydrate (15 g) is refluxed for about an hour, and then cooled for two hours at ambient temperature. The solid is filtered, and 62 g of substantially pure lurasidone oxalate is obtained after drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8](=[O:25])[CH2:9][NH:10][C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[O:25][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[N:10][CH:9]=1
Reactant: COc1ccc(OCC(=O)CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)o2)cc1OC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a toluene (10 ml) of the compound (0.250 g) obtained in Example 19-(4), Burgess reagent (0.281 g) was added and the mixture was stirred at 50° C. for 1.5 hours. After reversion to room temperature, the reaction mixture was concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.156 g, colorless oil.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:18]([C:20]2([CH3:23])[CH2:22][CH2:21]2)=[O:19])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.[H-].[Na+].Cl[CH2:27][C:28]1[N:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:34]([C:32]1[N:33]=[C:28]([CH2:27][CH:17]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[C:18]([C:20]2([CH3:23])[CH2:22][CH2:21]2)=[O:19])[CH:29]=[CH:30][CH:31]=1)#[N:35]
Reactant: COc1ccc(CC(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Reactant: N#Cc1cccc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl {5-methoxy-2-[2-(1-methylcyclopropyl)-2-oxoethyl]phenyl}carbamate (300 mg) in N,N-dimethylformamide (3.1 mL) was added sodium hydride (50-72% in oil, 50 mg) under ice-cooling, and the mixture was stirred for 1 hour. 6-(Chloromethyl)pyridine-2-carbonitrile (158 mg) was added thereto in one portion, and the mixture was gradually warmed to room temperature. 13 Hours later, to the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (271 mg). 1H-NMR (CDCl3) δ ppm: 0.62-0.73 (2H, m), 1.22-1.30 (5H, m), 1.57 (9H, s), 3.21 (1H, dd, J=8.2, 15.7 Hz), 3.54 (1H, dd, J=6.7, 15.7 Hz), 3.78 (3H, s), 4.68-4.78 (1H, m), 6.54-6.61 (1H, m), 6.95 (1H, d, J=8.5 Hz), 7.18-7.25 (1H, m), 7.33-7.40 (1H, m), 7.48-7.55 (1H, m), 7.64 (1H, t, J=7.8 Hz), 7.82 (1H, br s).