Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: CN
Reactant: OCCCCCCCCCCCBr
Solvent: CCO
Product: CNCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of 11-bromoundecanol (25.12 g, 0.10 mol) and methylamine (41% in water, 127 ml, 1.50 mol) in ethanol (50 ml) was heated for 7 h to 70° C. and stirred for a further 16 h at ambient temperature. The solvent was distilled off. After cooling the white solid was dissolved in caustic soda (2N, 200 ml) and diethyl ether (300 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The crude product was recrystallized from diethyl ether. 13.23 g (65.7 mmol, 67% yield) of a while solid (melting point: 58° C.) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.C(O[C:10]([N:12](C)[C@@H:13]([CH2:17][CH:18]=[CH2:19])[C:14]([OH:16])=[O:15])=O)(C)(C)C.[CH3:21]O>>[ClH:3].[CH3:10][NH:12][C@@H:13]([CH2:17][CH:18]=[CH2:19])[C:14]([O:16][CH3:21])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: C=CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CO
Product: C=CC[C@H](NC)C(=O)OC
Product: Cl
Temperature: 25 °C

Procedure:
Step G (1): Thionyl chloride (1.7 g, 14.4 mmol) was added to a round bottom flask charged with a solution of (S)-2-(tert-butoxycarbonyl(methyl)-amino)pent-4-enoic acid (1.66 g, 7.2 mmol) [Tetrahedron (1991), 47(29), pp. 5453-62] in MeOH at 0° C. After complete addition, the reaction mixture was heated at reflux for 2 h, then cooled to rt. The resulting solution was concentrated in vacuo and the residual volatiles were removed on high vacuum overnight to afford 1.32 g (quantitative yield) of the title compound as an off-white solid. LC-MS (M+H)+=143.96; [α]D +3.7 (c=7.57 mg/mL, methanol); 1H NMR (500 MHz, CD3OD) δ ppm 2.71-2.84 (m, 5H) 3.88 (s, 2H) 4.19 (t, J=5.65 Hz, 1H) 4.84 (s, 2H) 5.26-5.38 (m, 1H) 5.68-5.83 (m, 1H).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]=[C:24]2[CH2:29][CH2:30][OH:31])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:33].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@H:23]([OH:33])[C@@H:24]2[CH2:29][CH2:30][OH:31])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C2CCO)(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@H](O)[C@@H]2CCO)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 105.6 %

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-1-(2-hydroxyethyl)-3,4-dihydronaphthalene (1.0 g) in CH2Cl2 (30 ml) were added Na2CO3 (290 mg) and m-chloroperbenzoic acid (750 mg) at 0° C. After being stirred for 2 hours, the solvent was removed in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was dissolved into tetrahydrofuran (20 ml) and LiAlH4 (200 mg) was added at 0° C. After being stirred for 2 hours, the reaction was quenched by saturated potassium sodium tartrate solution. After filtration, the solvent was removed, and the residue was purified by chromatography on silica gel to afford (cis)-5-t-butyldiphenylsilyloxy-1-(2-hydroxyethyl)-2-hydroxy-1,2,3,4-tetrahydronaphthalene (1.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CCCCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
700 mg of the compound obtained in Step A are dissolved in 10 ml of ethyl acetate; 0.494 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.229 ml of butyl chloroformate is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:8]1[CH2:7][CH2:6][C:5]2[C:10]([CH:9]=1)=[C:1]([O:11][CH3:19])[CH:2]=[CH:3][CH:4]=2
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCCc2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1C=C(C1CNCCN1C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The tetralone (10 g; 56.8 mmol) was dissolved in 200 ml of toluene. To the solution then were added 13.0 ml (0.117 mol) of N-methylpiperazine followed by 25.1 g (0.13 mol) of p-toluenesulfonic acid. The mixture was stirred at reflux with constant removal of water. After 2 hours, the mixture was cooled to room temperature, and the volatiles were removed in vacuo to give 3-(N-methylpiperazinyl)-5-methoxy-1,2-dihydronaphthalene as a reddish-orange sludge.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:2]=[N-:3].N(CCO)=[N+]=[N-].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]1[NH:22][C:23]([CH3:29])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[Cl:30])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)/C=C(/C)N
Agent: [N-]=[N+]=NCCO
Solvent: CO
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Ethyl 4-(2-azidoethoxy)acetoacetate (46.4 g), prepared from 2-azidoethanol similarly to the method described in Preparation 3, was reacted with methyl 3-aminocrotonate (24.8 g) and 2-chlorobenzaldehyde (30.3 g) in methanol (150 ml) at reflux for 18 hours. After cooling to room temperature, the resulting solid was collected, washed twice with methanol and dried to give the title compound (28 g). The product could be crystallised from methanol, acetone or ethyl acetate. It was used directly.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]2[N:6]([C:10]([CH:29]3[CH2:32][C:31](=[O:33])[CH2:30]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1>>[Cl:3][C:4]1[C:5]2[N:6]([C:10]([C@@H:29]3[CH2:30][C@H:31]([OH:33])[CH2:32]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Product: O[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ethanolic suspension (20 mL) of 3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanone: (2.5 mmol) was charged with NaBH4(2.5 mmol) at rt. The reaction mixture was stirred at rt for 30 min until the reaction solution turned clear. The reaction mixture was quenched by an addition of Na2SO4.10 H2O and concentrated under reduced pressure. The crude mixture was dissolved in DCM, washed with water (3×15 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.93-7.87 (m, 3H), 7.58-7.52 (m, 3H), 7.47-7.45 (m, 1H), 7.37 (d, J=5.2 Hz, 1H), 4.44 (b, 1H), 3.37 (p, J=8.0 Hz, 1H), 3.03-2.96 (m, 2H), 2.60-2.53 (m, 2H); MS (ES+): m/z 427 (100) [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24]C(O)=O>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:2]=1[CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: COc1ccc(OC)c(CC2=C(C)C(=O)C3C=CC=CC3C2=O)c1
Yield: 80 %

Procedure:
As starting materials for the coupling reaction menadione and 2,5-dimethoxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:3, UV), 1.96 g (6.08 mmol, 80% yield) of P_TM60 were isolated as yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH:25]([CH3:27])[CH3:26])[C:35](=[O:37])[CH3:36])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N(c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1)C(C)C
Reaction time: 72 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-isopropyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken three days, with the temperature ramped from 50° C. to 85° C. An additional 0.20 mmol of acetyl chloride was added after the second day. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at room temperature, and filtered into an 8 mL vial. The reaction was concentrated via HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-isopropyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 423 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:49])C=1.C(OCC)(=O)C.CO>C(Cl)(Cl)Cl>[CH2:1]([N+:4]([O-:49])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCN(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CC[N+]([O-])(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Into a cooled solution of 5.0 g (9 mmol) of N-allyl-N,N-dioctadecylamine in 50 ml of chloroform at 0° C. under a nitrogen atmosphere is added dropwise with stirring a solution of 2.82 g (9 mmol) of 55% active m-chloroperbenzoic acid in 25 ml of chloroform. After the addition is complete (approximately 10 minutes), the resultant solution is allowed to warm to ambient temperature (about 22°-24° C.). The reaction is complete after about 2 hours when TLC analysis (silica gel, 19:1 v/v ethyl acetate:methanol) indicates the starting material has completely reacted. The reaction mixture is passed through a short column of basic alumina using chloroform as an eluent to give 5.2 g (quantitative yield) of the title compound as a white solid melting at 59°-64° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH3:23])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>CO.C1COCC1>[Br:25][CH2:23][C:22]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:24]
Reactant: CC(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCCCO)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
1-{3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone (O2.059; 3.4 g) was dissolved in methanol/THF (50/50 ml) and admixed while stirring with phenyltrimethylammonium tribromide (4.21 g). After stirring at RT for 3 h, 20% citric acid solution was added and the mixture was stirred for 1 h. Then EA was added and the EA phase was removed. The EA phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified by means of silica gel (80 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 2.49 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 2.5 °C
Yield: 100 %

Procedure:
A solution of 4-trifluoromethoxyaniline (XII) (14.66 mL, 108 mmol) in dry tetrahydrofuran (THF; 120 mL) was added, dropwise, to a cold (0-5° C.) stirred suspension of cyanuric chloride (II) (20.0 g, 108 mmol) and potassium carbonate (15 g, 108 mmol) in dry THF (400 mL). The reaction mixture was stirred for 3 h while slowly warming to ambient temperature. After stirring for 14 h at ambient temperature, the reaction mixture was diluted with ethyl acetate (400 mL) and then acidified with 1 N aqueous hydrochloric acid. The organic phase was separated, rinsed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue, an off white solid, was recrystallized from hot hexanes to afford (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (35.1 g, 99% yield): m.p. 119-122° C.; 1H NMR (CDCl3) δ 7.62 (d, J=3.3 Hz, 2H), 7.58 (d, J=2.2 Hz, 2H); ESI/MS 325 (M+H), 323 (M−H); Anal. Calcd. For C10H5Cl2F3N4O: C, 36.95; H, 1.55; N, 17.53. Found: C, 36.80; H, 1.53; N, 16.98.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][C:16]#[N:17])=[CH:9][CH:8]=1.[ClH:18]>ClC1C=CC=CC=1Cl>[CH2:13]([N:14]1[CH:15]=[C:16]([Cl:18])[N:17]=[C:1]([Cl:6])[C:2]1=[O:3])[C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cl
Reactant: N#CCNCc1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=c1c(Cl)nc(Cl)cn1Cc1ccccc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 92 g (725 mmol) of oxalyl chloride in 188 ml of 1,2-dichlorobenzene are added 26.5 g (145 mmol) of N-benzylaminoacetonitrile. The solution is heated to 60° C. for 20 min and to 90° C. for 6 h. It is allowed to cool and left at this temperature for 15 h. The solvent is removed under reduced pressure and the residue is eluted with silica gel and with a gradient from cyclohexane to 5:1 cyclohexane/ethyl acetate. The product fractions are combined and concentrated to dryness under reduced pressure. The residue is crystallized from diethyl ether. This affords 22 g (60% of theory) of the desired compound.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Sc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Sc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of (±) methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate (7.5 g, 16.70 mmol) obtained in example 4 in methanol (50 mL) was added aqueous 10% sodium hydroxide (20 mL). The reaction mixture was stirred at ca. 25° C. for 3 h. The solvent was removed under reduced pressure and the residue was acidified with 2 N hydrochloric acid, extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of dichloromethane and methanol (9:1) as an eluent to afford the title compound (6.0 g, 83%) as a white solid. mp: 79-82° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C@@H:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccccc2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3R)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate (8.4 g, 25.4 mmol) in CH2Cl2 (80 mL) at rt was added TFA (8 mL, 4.1 mmol). The mixture was stirred at rt overnight. Solvent was removed in vacuo. The residue was diluted with EtOAc, washed with 1N aqueous NaOH, brine; dried (Na2SO4) and concentrated to give the title compound as a light brown oil. 1H NMR (500 MHz, CDCl3): δ 7.58 (d, 1H), 7.49 (t, 1 H), 7.03-6.99 (m, 2 H), 4.97 (t, 1 H), 3.27-3.19 (m, 2 H), 3.02-2.92 (m, 2 H), 2.13-1.99 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[NH:14][C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:14]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0° C. was added NaH (12 mg of a 60% dispersion in oil, 0.30 mmol). After 5 min, ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowed to warm to ambient temperature and stirring was continued for 1 h. Saturated aqueous NaHCO3 (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 60:40, to give the title compound. MS: m/z=425 (M−C4H7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.Cl[S:15]([OH:18])(=O)=[O:16].P(Cl)(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:36]=1[NH2:37]>>[F:34][C:35]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:36]=1[NH:37][S:15]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:18])=[O:16]
Reactant: COc1cc(N)c2ncccc2c1
Reactant: Nc1c(F)cccc1F
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NS(=O)(=O)Nc2c(F)cccc2F)c2ncccc2c1
Yield: 3.6 %

Procedure:
In the similar fashion using route 19 general procedure 42, 6-methoxyquinolin-8-amine (Intermediate 23) (200 mg, 1.15 mmol), TEA (170 mg, 1.72 mmol), chlorosulfonic acid (150 mg, 1.27 mmol), PCl5 (260 mg, 1.72 mmol), DIPEA (300 mg, 2.23 mmol), 2,6-difluoroaniline (600 mg, 4.6 mmol) gave the title compound (15 mg, 4%) after purification by column chromatography with DCM/MeOH (1:0-97:3) as the eluent.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]6[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:30][CH:29]([O:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:40]=[CH:41][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:43])=[CH:8][C:9]=4[F:42])[CH:18]=3)=[N:26][CH:25]=2)[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(COC5CNC5)cn4)sc23)c(F)c1)NC1CC1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a suspension of 404 (221 mg, 0.365 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred for 4 h then concentrated, diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, rinsed with water and dried. The residue was purified by Biotage (SNAP 25 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 10/90 to 30/70), to afford the title compound 405 (155 mg, 84% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.55 (brd, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=7.2 Hz, 1H), 7.91 (dd, J=8.0, 2.4 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.24-7.18 (m, 1H), 6.65 (d, J=5.2 Hz, 1H), 6.62 (brd, J=2.8 Hz, 1H), 4.48 (s, 2H), 4.40-4.41 (m, 1H), 3.56-3.49 (m, 2H), 3.47-3.50 (m, 2H), 2.58-2.51 (m, 1H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 506.14 (M+H).